18-nor-d-homo-steroids



United States Patent ()fi Patented July 13, 1865 3,194,832 18-NOR-D-HOMO-S'I'EROIDS Hans Reimann, Bloomfield, and Eugene P. Oliveto, Glen Ridge, N.I., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Sept. 15, 1961, Ser. No. 138,273 18 Claims. (Cl. 260-488) This invention relates to novel l8-nor-D-horno-steroids and to methods for their manufacture. In general, this invention relates to l8-nor-D-homo-steroids having at least one unsaturation in at least one of rings A and B and possessing an oxygen function at C17 and an unsaturation stemming from C-17a, which steroids are valuable as therapeutics per se or as intermediates, and to methods for their manufacture including novel intermediates produced thereby. More specifically, this invention relates to S-dehydroand to A-ring unsaturated 17-keto-13(17a)-dehydro-lS-nor-D-homo-steroids possessing at C-11 an oxygen function or an unsaturation, and includes the tautomeric forms of the ll-keto derivatives. Thus, encompassed within this invention are S-dehydroand A-ring unsaturated 17-keto-18-nor-D-homo-l3 17a -dehydro-steroids having a configuration at carbon atoms 11 and 12 of the group consisting of:

of Formula I and of the aforementioned analogs thereof: 4

wherein B is a member of the group consisting of hydrogen, a-lower alkyl, fi-lower alkyl, a-halogen and ,e-halogen; X is a member of the group consisting of hydrogen and halogen; V is a member of the group consisting of H, 0:- lower alkyl, ,B-lower alkyl, a-halogen, S-halogen, and a-OY wherein Y is a member of the group consisting of hydrogen and an acid radical of an organic carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic :acids and aryl carboxylic acids; R is a member of the group consisting of hydrogen, lower alkyl, and an acid radical of an organic carboxylic acid having up to 8 carbon atoms selected from the group consistingof alkanoic acids and aryl carboxylic acids; W is a member of the group consisting of hydrogen and an acid radical of an organic carboxylic acid having up to 8 carbon atoms selected from the group consisting of alkanoic acids and aryl carboxylic acids; and Z represents a configuration at carbon atoms 11 and 12 of the group consisting of including tautomeric equivalents of the novel 17-keto-l8- nor-D-homo-13(17a)-dehydrosteroids containing the 11- keto-lZ-unsubstituted configuration, wherein A is a member of the group consisting of H and an acid radical of an acid of the group consisting of sulfonic acids and carboxylic acids having up to 12 carbon atoms.

Also included among the novel l7-keto-l8-nor-D-homol3(17a)-dehydrosteroids of our invention are the methyl analogs of Formulae I, H, and Ill, and particularly the 2- and 7-methyl analogs of the compounds of Formula I.

In this application whenever a compound name does not specifically designate the configuration at 6 and 16, both a and [-2 configurations are included. Thus, the compound name 6,16 dimethyl-18-nor-D-homo-l,4,l3(17a)-androstatriene-ll,8-ol-3,17-dione encompasses four isomeric configurations, namely 611,161: dimethyl 18 nor D-homo- 0 1,4,13 l7a)-androstatriene-11fi-ol-3,17-dione, 618,16/1 di methyl l8-nor-D-homo-l,4,l3( l7a)-androstatriene-l1B- ol 3,17 dione, 60,l6fi dimethyl l8 nor D 4 homo 1,4,13(17a)-androstatriene-l1fi-ol-3,17-dione, and 68,160;- dimethyl-18-nor-D-horno-l,4,13 (17a)-androstatriene11,8 ol3,l7-dione.

The term lower alkyl includes hydrocarbons having up to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl; and tertiary-butyl.

Typical esters at C-3 and Cl6 are lower alkanoates such as acetate, propionate, butyrate and enanthate or aromatic acyl radicals of aryl carboxylic acids having up to 8 carbons atoms such as benzoate and toluate.

Illustrative of the 11 ,B-acyl group which may be present are lower alkanoates such as formate, acetate, pro pionate, butyrate, isobutyrate, valerate, isovalerate, pival ate, caproate (n-hexanoate), enanthate; sulfonates such as 'methylsulfonate and p-toluenesul'fonate; aromatic acyl radicals of aryl carboxylic acids having up to 8 carbon atoms such as benzoate and toluate, as well as the acyl portions of dibasic acids such as succinate and phthalate Novel 18 nor D homo 13(l7a) dehydrosteroids of Formula I wherein Z is OH(BOH)CH are typified by 18-nor-D-horno-apdrostenes such as: 18- nor D homo 4,l3(l7a) androstadiene 11B ol- 3,17dione and the l-dehydro analog thereof, 905-1111010- 18 nor D homo 4,l3(17a) androstadiene 11/8- ol-3,l7-dione and the l-dehydro analog thereof, 9achloro 18 nor D homo 4,13(17a) androstadiene- 11B -ol 3,17 dione, 9oz bromo 18 nor D homo- 4,l3(17a) androstadiene 11/3 ol 3,17 dione, 16(0: and B chloro l8 nor D 1101110 4,13(17a)- androstadiene-l1,8-ol-3,17-dione and the 9e-fiuoroand 9'u-chloro-derivatives, thereof, 9a,16fl-difiuoro-18-nor-D- homo 4,13(17a) androstadiene 11B o1 3,17 dione, 18 nor D homo 4,6,13(17a) androstatriene 11,8- o1-3,17-dione, the l-dehydro and the 9a-iluoro-1-dehydro analogs thereof, 18-nor-D-homo-1,13(17a)-androstadiene 11/3 o1 3,17 dione, 60c methyl 18 nor D- homo 4,13(17a)-androstadiene llfl ol 3,17 dione, 60c 160a dimethyl 18 nor D homo 4,13(17a)- androstadiene-l1fi-ol-3,17-dione and the l-dehydro analog and 9a-fluoro-derivative thereof, 6u-fluoro-18-nor- D homo 4,13(17a) androstadiene 11B o1 3,17- dione and the l-dehydro analog thereof, 2u-methy1-18- nor D homo 4,13(17a) androstadiene 115 01- 3,17 ione, 9a fiuoro 161x acetoxy 18 nor D- homo 4,13(17a) androstadiene 11,8 ol 3,17 dione, 70c methyl 1 nor D homo 4,13(17a androstadiene -11/3 ol 3,17 dione and 60c fluoro 17,19 bisnor D homo 4,13(17 a) androstadiene 11B o1- 3,17-dione.

The 18-nor-D-homo-estrenes of Formula 11 wherein Z is CH(fiO1-I)CH .are exemplified by compounds such as 18-nor-D-hom0-1,3,5(10),13(17a)-estratetraene- 3,11e-diol-17-one and the 3-acetate and 3-benzoate esters thereof, 18-nor-D-homc-1,3,5(10),13(17a)-estratetraene 3,1113 diol 17 one 3 methylether, 18- nor D homo 1,3,5(10),13(17a) estratetraene 3, 11B-diol-17-one 3ethylether, 16(u and fi)-bromo-18-nor- D homo 1,3,5(10),13(17a) estratetraene 35,11 3- diol-17-one and the 3-ethylether and 3-acetate ester thereof.

Typical llfi-hydroxy steroids of Formula III are 18- nor D homo 5,13(17a) androstadiene 3,8, 11,3- diol-17-one, the 9a-fluoro-derivative thereof and their 3-acetate esters, 16a-bromo-18-nor-D-homo-5,13(17a)- androstadiene-SflJ1,8-diol-17-one and its 165-bromo epimer .and 18-nor-D-homo-'5,13(17a)-androstadiene-3fi, 11,9,16m-dil-17-one 3,16-diacetate and the 9oc-fl1lOrO-9'ocbromoand 9 x-chloroderivatives thereof.

Novel 18-nor-D-homo-l3 17a -dehydrosteroids of Formula I wherein Z is CH=CH- are 18-nor-D-homo androstenes such as 18-nor-D-l1omo-4,11,13(17a)-androstatriene-3,17-dione, its 9e-fluoroderivative and the 1-dehydro analogs thereof, 18-nor-D-homo,4,6,11,13- (17a.)-androstatetrsene-3,17-dione, and the l-dehydro analog thereof, 18-nor-D-homo-1,1l,13(17a)-androstatriene 3,17 dione, 90 fiuoro 6a,l6e dimethy-l 18- nor D homo 1,4,11,13(17a) androstatetraene 3,17- dione, and 9or-fluoro-16a-acetoxy-18-nor-D-horno-4,11, 13 17a) -undrostatriene-3, 17-dione.

Some 1l-dehydro-l8-nor-D-homo-estrenes of Formula II are such as 18-nor-D-homo-1,3,5(10),11,13(17a)- estrapentaene-3-ol-17-one and the 3-acetate and 3-benzoate esters thereof, 18-nor-D-homo-1,3,5(10),11,13(17a)- estrapentaene-3-ol-17-one 3-methyl ether, and 16a-bromo- 18 nor D homo 1,3,5(),11,13(17a) estrapentaene-3fl-ol-l7-one and the IGfi-bromo epimer thereof.

Exemplary of ll-dehydrosteroid of Formula III are 18 nor D homo 5,11,13(17a) andr-ostatriene 3,8- ol-17-one and the l6ct-br0mo-, 16,8-brom0, 16a-ch1oroand 16fi-chloro derivatives thereof, together with the S-acetate esters of the foregoing.

Novel 18-nor-D-homo 13(1721) dehydrosteroids of Formulae I and III wherein Z is are typified by 11-keto-androstanes such as 18-nor-D- homo-4,13(17a)-androstadiene-3,11,17-trione the 9mfiuoroderivative thereof and the l-dehydro analogs of the foregoing, 18-nor-D-hon1o-4,6,13 17a) -and1-ostatriene 3,11,17 trione, 6a fluoro 18 nor D homo- 1,4,13(17a) androstatriene 3,11, 17 trione, 90,1613- difluoro 18 nor D homo 4,l3(17a) androstadiene-3,11,17-trione, and 18-r1or-D-homo-5,l3(17a)-an- (III) Thus, when naming a novel 17-l eto-18-nor-D-homo- 13(17a)-dehydrosteroid of thi invention possessing an ll-keto group, the tautomeric forms are automatically included, namely the corresponding 11-keto-17-hydroxy- 12,17(l7a)-bis-dehydro and the corresponding ll-hydroxy 17 keto l1,13(l7a) bis dehydrosteroids. Therefore, the compound name, 18-nor-D-homo-4,13- (17a)-androstadiene-3,11,17-trione, also includes the structure 18 nor D homo 4,12,17(l7a) androstatriene- 17-ol-3,11-dione and 18-nor-D-homo-4,11,13(17a)-androstatriene-l1-ol-3,l7-dione.

The -18-nor-D-homo-steroids of our invention are conveniently manufactured by first preparing an ll-nitrite ester of an ll 8-hydroxy-l7-keto steroid of the estrene or androstene series possessing an unsaturation in the A-ring or at C-5 in the B-ring, and then subjecting the 11,6- nitrite-17-keto-androstene or 1lfi-nitrite-17-keto-estrene to ultraviolet radiation which possesses a band of radiation corresponding to at least some of the absorption bands of the nitrite radical; and isolating the llo-hydroxy 17 keto 18 nor D homo 13(l7a) dehydroandrostene or 11B-hydroxy-17-keto-18-nor-D-homo- 13(17a)-dehydroestrene thereby produced, i.e., a compound of Formulae I, II, and III wherein Z is The 11,8--acyloxy esters of Formulae I, II, and III i.e., wherein Z is CH(fl-OAcyl)-CH (e.g., the 11acetate, ll-methanesulfonate, and the ll-benzoate), are then conveniently prepared from the corresponding 1lfl-hydroxy-lS-nor-D-homo-steroids thus produced and isolated, by utilizing conventional techniques such as reaction with an acid anhydride (e.g., acetic anhydride) or an acid halide (eg, methanesulfonylchloride or benzoylchloride) in pyridine.

The novel llfl-hydroxysteroids of Formulae I, II, and III, prepared and isolated as described hereinabove may be converted to the corresponding 11-keto steroid, i.e., the 11,17-diketo-l3(17a)-dehydro derivatives (equivalent to the tautomeric 11-keto-l7-hydroxy-12,17(17a)- and the 11-hydroxy-17-keto-1Ll3(17a) bis dehydro forms) by oxidation of the ll-hydroxyl group utilizing known techniques such as chromic acid/sulfuric acid reagent in acetone.

The ll-dehydro-compounds of Formulae I, II, and III (Z is CH=.CH) are derived from the lie-hydroxy- 18-nor-D-homo-steroids to our invention by dehydration of the llfi-hydroxy function with, for example, perchloric acid in methanol. Novel C-ring saturated and unsubstituted 18-nor-D-homo-steroids may then be derived from the li-dehydro analogs of Formulae I and II by hydrogenation of the latter, for example usinghydrogen at atmospheric pressure with a catalyst such as palladium on calcium carbonate in a solvent such as benzene to selectively reduce the 11,12-double bond, giving the corresponding ring-C saturated and unsubstituted 18-nor-D- homo-13 17a) -androstene-17-ones.

Illustrative of our process is the following reaction sequence. Reaction of llfi hydrox -4androstene-3, 17-dione with nitrosyl chloride in pyridine at 30 to C. readily gives 11,8-hydroxy-4-androstene-3,17-dione 11- nitrite. The latter is irradiated with a Pyrex filtered 200 watt ultraviolet lamp, in a stream of nitrogen, in toluene at about 40 C. for about one hour. The solution is filtered from some insoluble material, then is concentrated to a residue which is crystallized from acetone diene-3,17-dione (a compound of Formula I wherein Z is CH(18OH)-CH which is convertible to the 11/3- acetate ester by reaction with a slight molar excess of acetic anhydride in pyridine at room temperature yielding 18-nor-D-1omo 4,13(17a) androstadiene-lidol-3,17- dione ll-acetate (Z is -CH(flOCOCI-I )-CH Dehydration of the 11,8-OH- product, i.e., -11[3-hydroxy-l8- nor-D-homo 4,l3(17a) androstadiene-3,l7-dione, produced and isolated as described hereinabove, is effected by allowing the compound to stand overnight in methanol containing a small amount of perchloric acid giving 18- nor-D-homo-4,l1,13(l7a)-androstatriene 3,17 dione (Z is -CH=CH). Oxodation of the 1lfl-hydroxy-18- nor-D-homo 4,13(17a) androstadiene-3,17-dione with chromic acid/ sulfuric acid in acetone yields a compound of Formula I, 18-n0r-D-hom0-4,13(l7a)-androstadiene- 3 ,l1,17atrione which is tuatomerically equivalent to 18-nor-D-homo-4- 12,17(17a)-androstatriene-17-ol-3,1l-dione, and 18-nor- D-homo-4,l1,13(17a)-androstatriene-1l-ol-3,l7-dione.

Similarly, lifl-hydroxyestrone S-acetate and 16a-methyl-5androstene-3B,11/3-diol-17-one 3-acetate are convertible to the corresponding ll-nitrite esters which, when dissolved in toluene and irradiated with ultraviolet light as described herein yield compounds of Formulae II and III,

respectively, having Z equal to -CH(;3OI-I)CH,

namely, 18-nor-D-homo-1,3,S 10) 13 17a) -estratetraene- 3,1 1/8-diol-17-or1e 3-acetate and l6oc-II16thYl-l 8-nor-D- tate. Dehydration of the aforementioned llfl-hydroxy- 18-nor-D-homoestrene and 1lfi-hydroxy-IS-nor-D-homo- S-androstene yields steroids of Formulae II and III wherein Z is -CH=CH-, namely, 18-nor-D-homo-1,3,5(10), 11,13(17a)-estrapentaene-3-ol-17-one B-ac etate and methyl-18-nor-D-homo 5,11,13(17a) androstatriene- 3fi-0l-17-one 3-awtate respectively. Alternatively, oxidation of the llfi-hydroxyl group yields novel compounds of Formulae II and III wherein Z is ('i-CH- i.e., l8-nor-D-horno-l,3,5 10) ,13 (17a)-estratetraene-3-ol- 11,17-dione 3-acetate and loot-methyl-lS-nor-D-homo-S, 13 17a -androstadiene-3fi-ol-1 1,17-dione 3-acetate respectively (equivalent to the respective tautomeric forms 18- nor-D-homo 1,3,5(l0),12,17(l7a) estrapentaene-3J7- diol-l l-one S-acetate and l8-nor-D-homo-l,3,5(l0),11, 13( l7a)-estrapentaene-3,l1-diol-17-one; and 16 x-rnethyllES-nor-D-homo 5,12,17'(17a) androstatriene-3,17-dioll l-one 3,8-acetate and 16rz-methyl-18-nor-D-hom0 5,l 1,

13(17a)-androstatriene-3,l1-diol-17-one S-acetate.

The necessary intermediates in our novel process are ll-nitrite esters of 1l-B-hydrox-l'fiketo-A-ring unsaturated androstanes, llfl-hydroxy 17 keto-S-dehydroandrostanes and 11,8-hydroxy estranes including compounds of the following Formulae IV, V, and VI as well as the 19-nor, A A A N- LS-dihydro analogs of Formula IV inclding the 3-ketal derivatives of the compounds of Formula IV and analogs thereof:

ONO

sod

Z wherein R, W, B, X, and V are as defined for Formulae I, II, and HI. Other ll-nitrite ester intermediates include l-nitrite esters of methyl analogs of the compounds of Formulae IV, V, and VI.

The l1-nitrite-l7-keto-estrane or androstane intermediates of our process are prepared by reacting a solution of the corresponding llB-hydroxy-N-keto steroid in pyridine, dimethylformamide, ethyl acetate, or other non-polar solvent with a nitrosyl halide, preferably nitrosyl chloride. The nitrosyl chloride or bromide used may be added to the llfi-hydroxysteroid solution in the same solvent as that used to dissolve the llfi-hydroxysteroid, or alternatively, it may be introduced as a gas into the steroidal alcohol solution. The formation of the lip-nitrite ester is usually rapid and generally complete Within /2 hour. Nitrosyl chloride is added until there is a color change to orange-brown or other color which persists, at such time it can be assumed that the Ills-nitrite has formed and the compound in solution is ready for separation and photolysis. The temperature at which the nitrite formation reactions are carried out range form usually --'*0 to +30 C. In general, when nitrosyl chloride is the reactant used, the reaction temperature is usually in the neighborhood from 20 C. to +10 C., and preferably at --l5 C. to -5 C.

. After completion of the formation of the llfl-nitrite ester, the nitrite is separated usually by adding water to the solution to precipitate the nitrite and by subsequent filtering followed by crystallization and recrystallization, if desired.

. When preparing the ll-nitrite ester intermediates it is preferable to protect any free hydroxyl groups elsewhere in the molecule. Thus, for example, prior to reaction with nitrosyl chloride and subsequent irradiation, the 3-monoesters of llfi-hydroxy-estrone and of 3,1l/3-dihydroxy-S-androstene-l7-one, e.g., the benzoate or acetate, are prepared by standard methods such as reaction of the corresponding 3-hydroxy compound with an acid chloride or acid anhydride, e.g., benzoylchloride and acetic anhydride. Removal of the protective ester grouping i effected preferably after irradiation of the 11-nitrite-17- keto steroid and isolation of the thereby produced novel 11 hydroxy 17 keto -18 nor D homo -13(l7a)- dehydrosteroid. Hydrolysis may be effected chemically by mild alkaline hydrolysis such as with methanolic sodium carbonate or in the case of the acetate esters, microbiologically utilizing Flavobacterium dehydrogenans (Rutgers Collection No. 130) utilizing procedures similar to those described in South African Patent No. 3,462/55.

If an ll-dehydrosteroid of Formula I, H, or HI is desired, simultaneous dehydration at C-ll together with hydrolysis of any ester group present may be accomplished with acid hydrolysis or stronger basic hydrolysis such as with perchloric acid or sodium hydroxide respectively. Thus, for example, 11/3-hydroxy-estrone (1,3, 5(l0)-estratriene-3,11e-diol-17-one) upon reaction with one equivalent of acetic anhydride and pyridine is converted to the corresponding 3-acetate ester which upon subsequent reaction with nitrosyl chloride in pyridine as described herein gives l,3,5()-estratriene-3,11/3-diol-17- one 3-acetate ll-nitrite. Irradiation with ultraviolet light of a toluene solution of the aforementioned 3-acetate l1- nitrite and isolation of the 18-nor-D-homo-l3(l7a)-dehydrosteroid thereby formed according to the process of our invention yields 18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,1lB-diol-l7-one 3-acetate which may be subjected to the action of sodium carbonate in aqueous met anol to give 18-nor-D-homo-1,3,5(10),13(l7a)-estratetraene-3,llfl-diol-17-one. Hydrolysis of the aforementioned 1lB-hydroxy-18-nor-D-homo estrene with perchloric acid on the other hand, yields the B-hydroxy-ll-dehydro compound, l8-nor-D-homo-1,3,5(10),1l,l3(17a)-estrapentaene-3-ol-l7-one.

According to the process of this invention, the steroidal nitrite esters of A-ring unsaturated androstanes, S-dehydroandrostanes, and A-ring unsaturated estranes, after preparation and isolation as described above, are dissolved in a non-reactive solvent prior to being irradiated by ultraviolet light. The solvent chosen preferably has a high degree of transparency to the ultraviolet radiation within the specified band of nitrite absorption. Solvents which may be used for the photolysis of the nitrite include acetic acid, acetone, acetonitrile, benzene, carbon disulfide, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, dimethylether, dimethylformamide, dioxane, ethyl acetate, Freon 113, heptane, methanol, ethanol, methylene chloride, and toluene. Gf these, benzone and toluene yield preferred results.

While the solvents used in the photolysis are ordinarily water-free, a small amount of moisture in the solvent used for photolysis does not ordinarily interfere with the progress of the ultraviolet activation and rearrangement of the nitrite in accordance with the present invention.

The ultraviolet radiation used to activate the nitrite radical is that band of radiant energy which corresponds to some or all of the ultraviolet absorption of the nitrite radical, and is from 3000 A. to 4400 A. This ultraviolet radiation activates the nitrite radical and causes it to leave the oxygen at C-ll with concomitant abstraction of a hydrogen from the 18-carbon by the resulting alkoxy group at C-ll; additionally the D-ring splits between C-13 and C-17 then recloses resulting in a bonding between original C-l8 and C17 (new C-17a and 17). This energy is conveniently supplied by a Hanovia high pressure mercury arc lamp with a Pyrex sleeve, while the nitrite to be reacted is contained in an ultraviolet transmitting vessel such as a water cooled Vycor-immersion well.

During the course of the photolysis of an llfi-nitrite ester of an estrane or androstane, a stream of nitrogen or other inert gas is generally bubbled through the solution (although not always necessary) to keep the nitrite solution protected by an inert atmosphere.

Our process whereby a steroidal l7-keto-1lB-nitrite estrane or androstane is irradiated by ultraviolet light is usually carried out utilizing a 200 watt mercury lamp as an ultraviolet light source with the irradiated material being dissolved in benzene or toluene and kept under an atmosphere of nitrogen. The reaction is usually carried out at temperatures ranging from l050 C. and preferably in the range of 18-40 C.

The photolysis of the nitrite ester which is carried out by irradiation with the selected band of ultraviolet radiation is monitored from time to time by infrared or ultraviolet spectrophotometry of an aliquot, and the reaction is complete when the infrared or ultraviolet absorption spectra lack the characteristic spectra of the nitrite radical.

By our process of photolyzing a l7-keto-1lfl-nitrite ester of an androstane or estrane, there is obtained a mixture of products, a major portion being a 17-keto-compound of Formula I, II, or III wherein Z is separable by filtration, partition chromatographic techniques or by fractional crystallization, or by a combination of these techniques. Our novel compounds are preterably crystallized from organic solvents such as ethyl acetate, acetone, acetone-hexane, methylene chloride, methylene chloride-hexane, methylene chloride-ether and the like, or chromatographed on Florisil using eluting solvents and solvent mixtures such as hexane, ether-hexane, ether, ether-methylene chloride, methylene chloride, methylene chloride-acetone and the like. Alternatively, our novel 18-nor-D-hom0-13(l7a)-dehydro-androstenes and estrenes may be isolated using a partition chromatographic system on Chromosorb, such as ligroin, propylene glycol, toluene-propylene glycol or the like. When chromatographic techniques are used, fractions are monitored by infrared and ultraviolet spectroscopy to determine the 9 zones containing the desired 1lfi-hydroxy-l8-nor-D-homol3 l7a)-dehydrosteroids.

According to our process, the irradiation of an organic solution of the ll-nitrite ester of an 11-hydroxy-17-keto- A-ring unsaturated or S-dehydro-estrane or androstane produces an 1lfi-hydroxy-l8-nor-D-homo-13(17a)-dehydroandrostane or estrane of Formulae I, II, and III wherein Z is -CH(,8OH)CH The novel 18-nor-D-h0- mosteroids of our invention having an acyloxy group or a keto group at C-ll, or a double bond between the 11- and 12-caroons are derived from the novel llfl-hydroxy- 1S-nQr-D-hOmo-androstanes and estranes utilizing conventional techniques as heretofore described.

The necessary starting compounds in our process of preparing the novel 18-nor-D-homo13-(17a)-dehydro steroids of our invention are ILB-hydroxy-17-keto-A-ring unsaturated androstanes, 1lfi-hydroxy-l7-keto-5-dehydroandrostanes, or 1lfi-hydroxy-l7-keto-A-ring unsaturated estranes which are convertible to the corresponding 11- nitrite intermediates of formulae III, IV, and V. Many 11,6-hydroxy-1'7-keto androstane and estrane starting compounds are known; for example, androstanes such as 4- i androstene-l1,6ol-3,17-dione and the 9a-fiuoroand 9achloroand 9u-bromo-derivatives thereof, 19-nor-4-androstene-.11fl-ol-3,17-dione, 1,4-a11drostadiene 11B el- 3,17- dione and the 9a-fiuoro-deriva-tive thereof, 1,4,6-andro- 'statriene-1:115ol-3,l7-dione and its 9u-fluoro-derivative, 6ot-methyl 4 androstene-l1fl-o1-3,l 7-dione, 6oz-flll0104- andr-ostene-l1/3-ol-3,17-dione and the 19-nor and l-dehydro analogs thereof, 6fi-fluoro-1,4-androstadiene-11B- 0l-3,17-dione, 2a-rnethyl4 androstene-1 1(3-01-3,17-dione, 16a-fluoro-4-androstene-l1,B-ol-3,11 7-dione and the 16/3- fiuoro epimer thereof, 9a,16or-difluoro-4-androstene-11B- 0l-3,17-dione and the 16fi-fluoro epimer thereof, 9a-

Some 11B-hydroxy 17-keto A-ring unsaturated estranes known in the art are llfi-hydroxy-estrone (1,3,5(10)- estratriene-3,11/3-diol-17-one) and the 3-acetate and 3- benzoate esters thereof as Well as 3-lower alkyl ethers thereof such as the 3-rnethyl and 3-ethyl ethers, 6afluoro-l1fi-hydroxy-estrone and l-methyl-l 1 fi-hydroxyestrone 3-rnethyl ether.

Other 1l/8-hydroxy-l7-keto-androstane starting steroids may be prepared from known 11,8,17u,21-trihydroxy-20- keto pregnanes by the oxidative degradation of the C-17 side chain utilizing sodium bismuthate. Thus, G-dehydrocortisol (4,6-pregnadiene-11B,l7a,2l-triol-3,20-dione) and 16u-methylprednisolone (loot-methyl 1,4 pregnadiene- 11p,17a,2l-triol-3,20-dione), upon reaction with sodium ing 1 1-desoxy-l7-keto androstanes by hydroxlyating HliCI'Or biologically at 0-11 with the acid of microorganisms such as Curvularia lunam (N.R.R.L. 2380) using procedures analogous to those described in US. Patent No. 2,658,023. Thus for example, 16erand 16,8-chloro-4-androstene- 10 H 3,17-dione may be hydroxylated with Curvularia lunata to give respectively 16a-chloro-4-androstene-11,B-o1-3,17 dione and 16/3-chloro-4-androstene-11fl-ol-3,17-dione.

Additionally, 1lfi-hydroxy-l7-keto-estranes and 11,8- hydroxy-l7-keto-S-dehydro-androstanes may be conveniently prepared from the corresponding 11-desoxy-17-ketoestranes and 1l-desoxy-17-keto 5 dehydro-androstanes utilizing adrenal perfusion techniques such as described in US. Patent No. 2,671,752. An alternative method for preparing an ll-hydroxy-17-keto-estrane is by subjecting the corresponding 1lfl-hydroxy-l7-keto-l9-nor-4-andro stene to the action of Corynebacterium simplex according to known techniques.

Some typical 1l-desoxy-17-keto androstanes and 11- desoxy-17-keto-estranes which may be ll-hydroxylated as described above to give the necessary -hydroxy-17- keto-androstane and 1lfl-hydroxy-17-keto-estrane precu sors of the ll-nitrite intermediates for our process are S-andr-ostencs such as S-androstene-Iifi-ol-17-one, 16ahydroxy-5-androstene-3,B-ol-l7-one, l6a-bromo-5-androste11e6fl-ol-17-one 3-acetate and the 16B-bromo epimer thereof, 16a-chloro-S-androstene-3B-ol-17-one B-acetate and its 16B-chloro epirner; 4-androstenes such as 1600- bromo-4-andr-ostene-3,l7-dione and the 16fl-bromo epimer thereof, 16rx-chloro-4-androstene-3,l7-dione and its chloro epimer, and 16fi-rnethyl-19-nor-4-androstene-3,17- dione; as well as estranes such as l6B-methyl-l,3,5(l0) estratriene-3-ol-17-one and the B-methyl ether derivative thereof, 16u-bromo-1,3,5(10)-estratriene-3-ol17-one 3- acetate and the l6B-bromo-epimer thereof and 6B-methyl- 1,3,5 (10)-estratriene-3-ol-17-one and the 6-dehydro analog thereof. I

When preparing an 18-nor-D-homo-17-keto-13(17a)- dehydrosteroid of our invention which is substituted at one or more of carbon atoms 2, 4, 6, 9, and 16, for example, such as indicated in Formulae I-VI, it is preferable to have all the desired substituents in the 11-nitrite-l7-keto intermediate prior to irradiation with ultraviolet light, although they may be introduced at any time during the process described herein. When starting 11B-hydroxy-17-ketoandrostanes or estranes or corresponding 11-desoxy-17- keto-androstanes or estranes or 1lfi,17a,21-trihydroxy-20- keto-pregnane precursors are not known which have a desired combination of derivatives at one or more of carbons 2, 4, 6, 9, 11, 12, or 16, for example, these groups may be introduced into the molecule utilizing procedures known in the art. Thus, a 6-substituent is introduced into a 3-keto-A -steroid to form a corresponding 6-substituted- 3-keto-A -steroid by employing known chemcal techniques. For exemple, an 11fi-hydroxy-l7-keto-androstane such as 16,8-fluoro-4- androstene-l1fl-ol-3,17-dione is treated with ethylene glycol by known procedures to form the 3,17-bis-ethylene ketal derivative which, in turn, is epoxidized on treatment with a peracid such as peracetie or preferably monoperphthalic acid to give the epoxy derivative, 504,6oc-6POX -16fl-fluoro 4 androstene-ll[3-ol- 3,17-dione-3,17-bis-ethylene ketal. From this epoxy intermediateboth the 6-methyl and -6-halogeno substituents (e.g., 6-fluoro, 6-chloro, and 6-bromo) may be introduced into the androstane nucleus. Thus, the action of a hydrohalic .aid, e.g., hydrofluoric acid, on the epoxy bis-ethylene ketal intermediate simultaneously hydrolyzes the bisethylene ketal groups and opens the epoxy ring yielding the corresponding 5a-hydroxy-6B-halogeno intermediate,

e.g., 5a-hydroxy-6fi,16,8-difluoro-4-androstane-3,17-dione; whereas addition of a Grignard reagent such as methyl magnesium iodide with subsequent hydrolysis yields the 5u-hyd-roxy-6B-methyl compound, e.g., 65-methyl-16flfluoro-4-androstene 5mldfi-diol 3,17 dione. A reagent such as ethanolic hydrochloric acid on the 5a-hydroxy-6B- substituted-intermediate simultaneously dehydrates the 5mhydnoxy group and epimerizes the 6,8-substituent to yield, respectively, 6oc,16,8-difluoro 4 androstene-11,8-ol-3,17- dione and 6oz-methyl-16B-tluoro-4-androstene-1Idol-3,17- dione. On the other hand, when Soc-hYdIOXY-fifl-SubStituted androstane intermediates are treated with, for example, approximately 90 percent acetic acid or with thionyl chloride in a cold basic medium such as pyridine there are obtained GtE-substituted androstanes such as 6,8,16/3-difiuoro-4-androstene-11B-ol-3,17-dione and 6emethyl 16B fiuoro-4-androstene-115-01-3,17-dione. The 6u-substituted-17-keto androstanes may also be prepared from the corresponding opt-substituted isomers by means of alcoholic solutions of acids or bases such as ethanolic hydrogen chloride and ethanolic potassium hydroxide.

Introduction of a 9a-halogen group into a 11/3-hydrox jsteroid may be effected by dehydrating an llfi-hydroxyandrostene or an llB-hydroxyestrane such as 16 8-methyl- 19-nor-4-androstene-l1fl-ol- 3,17-dione and 3-rnethoxy- 16,8-methyl-1,3,5(10)-estratriene-11B-ol-17-one (prepared by the action of Curvularia lrmata on the corresponding 1l-desoxy-19-nor-4-androstene and l,3,5(lO)-estratriene respectively) with an alkyl or aryl sulfonyl chloride (e.g., methane sulfonyl chloride) in an alkaline organic medium such as in pyridine to effect the production of the corresponding 9(11)-dehydro-intermediate, e.g., 16/3-rnethyl- 19-nor-4,9(11)-an-drostadiene-3,17-dione and 3-methox 16/3-methyl-l,3,5(10),9(11)-estratetraene-17-one, respectively. Placement of a halogen, and preferably bromine at this point in the procedure, at the 9a-carbon position is accomplished by conventional means, such as by reacting the 9(11)-dehydrosteroid with hypobromous acid which can be prepared in situ from the reaction of N-bromoacetamide and perchloric acid yielding directly the corresponding 9rx-bromo-11fi-hydroxy derivative, e.g., 16fl-methyla-bromo 11p hydroxy-19-nor-4-androstene-3,17-dioneand 3-methoxy-16fi-methyl 9a bromo 11/3 hydroxy- 1,3,5(10)-estratriene-17-one, respectively. Other 9a-halogeno derivatives are obtained from 9ot-bromo-11B-hydroXy steroids such as the aforementioned, by refluxing the 9abromohydrins with mild alkali, such as sodium acetate in methanol, to form the corresponding 9,8,11,8-oxido derivatives, e.g., 165-methyl-9B,1lli-oxido-19-nor-4-androstone-3,17-dione and 3-methoxy-16/3-methyl-9B,1lfl-oxido- 1,3,5(10)-estratriene-17-one respectively. These latter compounds are then reacted with hydrogen fluoride in chloroform with or without ethanol and/or tetrahydrofuran to form fiuorhydrins, e.g., 16fl-methyl-9a-fiuor0- llfi-hydroxy 19 nor 4 androstene-3,17-dione and 3- rnethoxy-lofi-methyl 9a fiuoro-11,8-hydroxy-1,3,5 (10)- estratriene-17-one respectively. Similarly, the substitution of anhydrous hydrogen chloride for hydrogen fluoride in this reaction results in the production of the corresponding 9a-chloro-derivatives, 16fi-rnethyl-9a-chloro-1l d-hydroxy-l9-nor-4-androstene-3,17-dione and 3-methoxy-16flmethyl-9a-ehloro 11B hydroxy-1,3,5(10)-estratriene- 17-one.

Substituents such as ot-hydroxy, oz and ,B-lower alkyl, and c and ,B-halogeno may be introduced into the steroid nucleus at (L16 utilizing known procedures. For example, a hydroxyl group may be introduced microbiologically into the 16ot-positien of a 16-desoxy-androstane or 16-desoxy-estrane by the action of microorganisms such as Streptomyces halstedii, A.T.C.C. 13, 499, or Streptomyces halstedii, N.R.R.L. B-1238, utilizing procedures similar to those described in US. Patent No. 2,991,230. Thus, 60c methyl 4 androstene-l1fl-ol-3,17-dione, and 3-mothoxy-1,3,5()-estratriene-11,8-ol-17-one upon reaction with Streptomyces halsredii, A.T.C.C. 13, 499 are each converted to their corresponding 16 t-hydroxy derivatives, i.e., 6u-methyl-4-androstene-11B,16a-diol-3,17-dione and 3-methoxy-1,3,5(10) BS'EIELtIlfiDE-l1,1606-dl0l-l7-OI16 respectively. The loa-hydroxyl group thus introduced into the molecule is preferentially esterified prior to preparing the necessary ll-nitrite intermediate for irradiation with ultraviolet light according to the process described herein. Accordingly, the 11p,16,8-dihydroxy intermediates prepared as described above are preferentially first esterified with one equivalent of acetic anhydride in pyridine, for example, to yield their respective 1lfldrydroxy-loct-aeetoxy derivatives, i.e., 6ct-methyl-4-androstene-115,16oc-dio1-17- one 16-acetate and 3-methoxy-1,Z-,5(10)-estratriene-l1,8, 16a-triol-17-one 16-acetate. Conversion to the corresponding 11-nitrite esters followed by irradiation with ultraviolet light in the manner of the process of this application yields compounds of our invention, namely, 6&- methyl 16a acetoxy-18-nor-D-homo-4,13(l7a)-androstadiene-llB-ol-U-one and 3-methoxy-16a-acetoxy-18- nor-Dhomo-1,3,5(l0),13(17a) estratetraene-11fi-ol-17- one respectively. Mild hydrolysis such as with potassium bicarbonate in methanol then converts with 16a-aeyloxy group to the corresponding 16a-hydroxy derivative, 60crnethyl-lS-nor D homo-4,13(l7a)-androstadiene-1lfl, 16a-diol 17 one and 3-methoxy-18-nor-D-homo-1,3,5 (l0),13(l7a) estratetraene-llfl-16m-diol-17-one respectively.

Introduction of a halogen into the 16-position may be effected by any of several known techniques. For example, 16ot-hydroxyandrostanes or estranes such as 6w methyl 4 androstene-l1fi,16a-diol-3,17-dione and 3- methoxy 1,3,5(10) estratriene-l1,8,16a-diol-17-one are convertible to their respective 16-mesylate esters upon reaction with methanesulfonyl chloride in pyridine which, in turn, may be reacted with a halide salt such as potassium fluoride in a manner similar to that described in Patents Nos. 2,857,403 and 2,901,494 to obtain both 16c:- and 16,8-fluoro-derivatives, e.g., 6ot-methyl-l6-iiuoro-4-androstene-11fl-ol-3,17-dione and 3-1neth-oxy-16-fiuoro-1,3,5 (1))-estratriene-1lfi-ol-17-one. Similarly, reaction of loot-mesyloxyandrostanes or 16a-mesyloxyestranes with other halide salts such as calcium chloride, lithium bromide, or sodium iodide yields the corresponding 16B- chloro-, 16,8-bromo-, or lfi-iodo-derivatives respectively. Alternatively, enol esters of 17-keto-androstanes or estranes, i.e., 17-acylcxy-16-dehydroandrostanes or estranes may be reacted with bromine in methylene chloride, for example, or with chlorine in acetic acid according to known techniques to obtain the corresponding 16ot-bromo and 16a-ehloroandrostane or estrane derivatives.

The tom-lower alkyl and lcfi-lower alkyl-11,5-hydroxy- 17-ketoandrostane derivatives are conveniently obtained via the sodium bismuthate oxidative degradation of the 17-side chain of the corresponding 16-alkyl17a-hydroxypregnanes according to procedures described in copending application of Rausser et al., Serial No. 776,446, filed November 26, 1958. The aand IGfi-lower alkylestranes may then be derived from the corresponding 3- keto-16-alkyl-1,4-androstadienes by pyrolysis in mineral oil by known techniques. For example; 16a-methylprednisolone reacted with sodium bismuthate in acetic acid yields Mos-methyl-1,4-androstadiene-11,B-ol-17-one which upon pyrolysis in mineral oil at about 660 C. yields the corresponding 16-alkyl-estrane, 16a-methyl-L3, 5(10)-estratriene-3,11,8-diol-1'7-one.

in preparing the l-dehydro analogs of the novel compounds of our invention falling under Formula I, the A bond may be introduced at various stages during the synthesis of the compounds, and preferably at the earlier stages prior to irradiation with ultraviolet light. The dehydrogenation may be accomplished by known chemical means such as by utilizing selenium dioxide or dichlorodicyanobenzoquinone or microbiologically with an organism such as Corynebacterium simplex (A.T.C.C. 694-6). For example, 6a,9oa-diflUOl'O-4-Eli1df08t6l1fi-l 1fl,ica-diol-3,17- dione (prepared by oxidative degradation utilizing sodium bismuthate, of 6a,9u-difiuorG- i-pregnene-11fl,16x,17a, 2l-triol-3,2i)-dione) and 2a-methyl-4-androstcne-l l fi-ol-S, 17-dione may be micrcbioiogically dehydrogenated with an organism such as Corylzebacterium simplex (A.T.C. C. 6946) in a manner similar to that described in US. Patent No. 2,837,464 to yield 606,9Ct-dlflllOIO-1,4-21Ildl'OStildlens-11/3,16a-diol-3,17-dione and Z-methyl-1,4-androstadiene-11,6-ol-3,17-dione respectively.

The A -4-,5-dihydro androstene analogs of the compounds of Formula I may be obtained from the correspending 3-keto-4-androstenes of Formula I; and the conversion from 3-keto-4-androstene to 3-keto-l-androstene must be effected in the early stages of the process of this invention, preferably prior to the preparation of the ll-nitrite ester of the starting 11-hydroxy-17-keto-androstanes. For example, 9a-lluoro-16a-acetoxy-4-androstene-1 15-01-3, 17- dione subjected to the action of a catalyst such as palladium in a solvent such as ethanol, ethyl acetate or tetrahydro furan yields 9a-fiuoro-16a-acetoxyandrostane-l l/3-ol-3,l7- dione. Reaction of the aforementioned androstane with one equivalent of a halogen such as bromine yelds the 2-bromo-analog which is dehydro halogenated with a reagent such as collidine or dimethylformamide in the pres ence of calcium carbonate yielding 9a-fluoro-l6a-acet0xyl-androstene-ll,B-ol-3,l7-dione. This starting compound is then convertible to the corresponding ll-nitrite ester which, in turn may be photolyzed by ultraviolet light according to our process to yield a novel compound of our invention, namely, 9a-fluoro-l6a-acetoxy-18-nor-D-homo- 1,13 (17a)-androstadiene-11B-ol-3,17-dione.

A o-dehydro-bond is preferentially introduced into an l1fl-hydroxy-l7-keto androstane of Formula IV prior to esterilication with nitrosyl chloride and subsequent irradiation with ultraviolet light. The 6-dehydro starting compounds may be prepared directly from the corresponding 3-keto-4-androstene-l1flol-l7-one or 3-keto-1,4- androstadiene-llB-ol-17-one (e.g., 6a-methyl-4-androstene-1lB-ol-3,l7-dione and 9ot-fiuoro-l6fi-chloro-L4-androstadiene-llB-ol-Q,l7-dione) by dehydrogenation with an agent such as chloranil in refluxing xylene; or by the allylic halogenation with agents such as N-bromosuccinimide to form the corresponding 3-keto-6-bromo-4-androstone or 1,4-androstadiene (e.g., 6u-methyl6-bromo-4- androstene-ll[3-ol-3,l7-dione) and subsequent dehydrohalogenation in refluxing collidine or lutidine to give 6 dehydro compounds, e.g., 6a-methyll,6-androstadienel1fi-ol-3,17-dione.

A 1,4-dienone of an llB-hydroxy-17-keto androstane from whence is derived an lie-nitrite of Formula IV may be converted to an llfi-hydroxy-l7-keto-l9-nor-4-androstene or an llp-hydroxy-l7-keto-l,3,5(l0)-estratrieneprior to esterification with a nitrosyl halide and irradiation with ultraviolet light according to our process to obtain the novel l9-nor analogs of Formula I and the l8-nor-D- homo-l3(l7a)-dehydroestrenes of Formula II. For example, 9zx-fitlOfO-1 6a-methyl- 1 ,4-androstadiene-1 lfi-ol- 3,17-dione (derived by the oxidative degradation with sodium bismuthate of 9a-fluoro-l6a-methyl-l,4pregnadiene-l13,17a,21-triol-3,20-dione) is pyrolyzcd either in the solid state or in an inert solvent to eifect elimination of the l9-methyl and concomitant aromatization of the A-ring to produce the llfl-hydroxy estrane, 9a-fluoro-l6u-methyl-1,3,5(lO)-estratriene-3,1lp-diol17-one, which may be reacted with nitrosyl chloride to form an ester of Formula V. Conversion of the aforementioned estratriene to its 3-methyl other with dirnethylsulfate in alkaline methanol,

then protection of the 17-ketone by ethylene glycol ketalformation followed by reaction of the resulting S-methoxy- 9ot-fluoro-l6ot-rnethyl-l,3,5(l0)-estratriene 11p 01-17- one-17-etl1ylene glycol-ketal with liquid ammonia and lithium in the presence of a proton donor such as ethanol, with subsequent treatment with a reagent such as methanolic hydrochloric acid yields a l9-nor-l le-hydroxy compound, 90: fluoro 16a methyl-19-nor-4-androstenell,8-ol-3,l7-dione, precursor of an ll-nitrite ester of the 19-nor analog of Formula IV.

Our processwhereby an ll-nitrite ester of an llfi-hydroxy-l7-keto steroid such as those of Formulae IV, V, and V1, is irradiated with ultraviolet light and isolated to give 18-nor-D-homo-l3'(l7a)-dehydrosteroids such as those of Formulae I, II, and III, is not limited to the preparation of the compounds defined by Formula I, II, and III. Byour process an llfi-hydroxy-l7-keto steroid may be con verted to the corresponding ll-nitrite ester which, upon irradiation with ultraviolet light, as described hereinabove,

lid

is converted to the corresponding Ill-nor D homol3(l7a)-dehydrosteroid. Thus, for example, lla-methyl- 4-androstene-1l/i-ol-3,17-dione, 4-chloro 4 androstenellfl-ol3,l7-dione, Z-androstene-l1,6-ol-l7-one, 4-andro stene-llfi-ol-l7-one and the Qm-fiuoro analog thereof, 5(10)-androstene-l1,8-01-17-0ne and the 9a-fiuoro analog thereof may be converted to their respective ll-nitrite esters which upon irradiation with ultraviolet light yield, respectively, lla-methyl-ll-nor D homo-4,13(l7a)-androstadiene-l1,6-ol-3,l7-dione, 4-chloro-l8-nor-D-homo- 4,l3(l7a)-androstadiene llfi ol-3,l7-dione, 18-nor-D- homo-2,13 17a) -androstadiene-l 1,8-ol-l7-one, 18-nor-D homo-4,13(l7a)-androstadiene-l1B-ol-l7-one and the 9mfiuoro analog thereof, l8-nor-D-homo-5(l0),l3(l7a)-androstadiene-llfl-ol-l7-one and the 9a-fiuoro analog thereof.

The 18-nor-D-homo-l3 l7a)-dehydroandrostanes of Formulae I and III and the l8-nor-D-homo-l3(17a)-dehydroestranes of Formula II are valuable therapeutic agents.

The novel 18 nor D homo-l3(17a)- el1ydro-4-androstenes of Formula I, and the 18-nor,A ,A ,A -bis-dehydro and SOL-A1 analogs thereof as well as the novel 18- nor-D-homo-l3 (17a) -dehydro-5-androstenes of Formula III all are valuable therapeutic agents in that they possess a favorable anabolic/androgenic therapeutic ratio (i.e., they have a very high anabolic to androgenic ratio) and are thus therapeutically valuable for the treatment of disorders requiring high anabolic activity with a minimum of concomitant androgenic effects. Our l8-nor-D-homol3(17a)-dehydroandrostenes are therefore useful in the treatment of geriatric disorders, debilitating diseases, severe infections, as well as post-surgical therapy. The novel compounds of Formulae I and Ill are advantageously used in place of anabolic/androgenic agents used in known anabolic/androgenic pharmaceutical preparations such as 17u-ethyl-l9-nortestosterone. They are preferably administered orally in the form of tablets, capsules, and the like in dosages ranging from 0.5 mg. to 20 mg. depending on the age of the patient and the severity of the illness.

The l8-nor-D-homo-l3(l7a)-ciehydroestranes of Formula II are useful, therapeutically active compounds in that they exhibit estrogenic activity. Our compounds of Formula II are advantageously used in place of known estrogenic agents such as estradiol, and ethinylestradiol and may be administered in the same manner as these aforementioned estrogens.

The preferred species of the compounds of our invention are those having an ll-hydroxy group at C-ll since in addition to being therapeutically valuable per se, they are valuable as intermediates in preparing the novel ll-keto and ll-dehydro l8-nor-D-homo-compounds of Formulae I, ii, and III.

The following are examples which illustrate our invention. It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art; the invention is therefore to be limited only by the scope of the appended claims.

EXAMPLE 1 A. 4-andr0sfene11,B-0l-3,17-di0ite l1-nizrite.-To a solution of l g. of 4-androstene-115-ol-3,l7-dione in 10 ml. of dry pyridine chilled to -30 C. is added dropwise a chilled saturated solution of nitrosyl chloride in pyridine until the reaction mixture has a definite orange color. During the addition, the reaction solution is allowed to warm to l0 C. and is stirred at this temperature for /2 hour after the addition is complete. The reaction mixture is poured into ice water. A solid sep sue-a arates which is filtered, Washed with Water and dried to give 4-androstene-1l5-ol-3,17-dione ll-nitrite, MP. 155- 160 0., [a1 (chloroform) +249 )t Nujol 5.76, 5.96, 6.07, 6.18

B. 18 nor D homo 4,13(17a) androstadiene- Z1-ol-3,17-dione.A solution of 916 mg. of 4-androstene-llfi-ol-3,l7-dione ll-nitrite in 200 ml. of toluene under a blanket of nitrogen is irradiated for one hour at 40 C. with a 208 Watt mercury lamp provided with a Pyrex filter. The solution is cooled, filtered, and the insoluble residue discarded. The remaining filtrate is evaporated in vacuo to a residue which is recrystallized twice from acetone to give l8-nor-D-homo-4,13(17a)- androstadiene-l1,8-ol-3,l7-dione, Ml. 269273 C.,

[0111) (pyridine) +134. xgfgg 241m (633,500) ANujol 3, 6, 6.1, 6.2,...

EXAMPLE 2 .ld-nor-D hmo-1,4,13 (1 7a -androstatriene-11,8 oZ-3,17-di0ne A. 1,4-androstadieneJ1,6-ol-3,17-dione 1 1-nitrite.A solution of 6 g. of 1,4-androstadiene-l1fl-ol-3,17-dione in 60 ml. of dry pyridine is reacted with nitrosyl chloride in pyridine at 30 C. to 10 C. according to the procedure of Example 1A. The resultant product is isolated and purified in the described manner to give 1,4- androstadiene-llfi-ol-3,l7dione 1l-nitrite, MP. 1G5- 109 (2.,

[a1 (chloroform) +179 A332 239 mu (16,400) hNujol 5.72, 5.76, 6.0, 6.10, 6.22

B. 18 nor D homo ],4,13(17a) androstatriene- 115-013,] 7-dione.-A solution of 700 mg. of 1,4-androstadiene-llfl-ol3,l7-dione ll-nitrite in 201) ml. of toluene under a blanket of nitrogen is irradiated With a 200 Watt mercury lamp in the manner of Example 13. The resultant reaction mixture is filtered and the insoluble residue discarded. The filtrate remaining is concentrated to a residue which is recrystallized from acetone to give 18- nor D homo l,4,l3(l7a) androstatriene 11p ol- 3,17-dione, Ml. 254-257 C.,

[afl (pyridine) +s5 3 5 243 my. (e32,600) kNujol 2.97, 6.02, 6.12, 618p.

EXAMPLE 3 90a halogeno 18 nor D homo 4,l3(17a) androstadiene 11 6 ol 3,17 dione and 90: halogeno l8- rzor D homo l,4,13(17a) androstatriene 11/3- 01-3,]7-dione A. 9a halogeno 4 androstene 11,8 ol 3,1 7 dione 11 nitrite and 90a hal'ogeno 1,4-ar2dr0szadiene 11,8- ol-3,17-dz'one 11-nitrite.-A solution of 9m-fluoro-4-androstene-l1B-o1-3,l7-dione in pyridine is reacted with nitrosyl chloride in pyridine at 30 C. to -l0 C. according to the procedure of Example 1A. The resultant product is isolated and purified in the described manner to give 9a-fiuoro-4-androstene-1lfl-ol-3,17-dione ll-nitrite.

In a similar manner, 9u-chloro-4-androstene-11,8-01-3, 17-dione. 9u-bromo-4-androstenel1,B-ol-3,17-dione and 9u-fiuoro-l,4-androstadiene-1l,8-ol-3,17-dione are reacted With nitrosyl chloride in pyridine to give 9oc-Ch10I0-4- androstene-l1B-ol-3,17-dione ll-nitrite, 9a-bromo-4-androstene-llfi-ol-3,17-di0ne ll-nitrite, and 9a-fluoro-l,4- androstadiene-l lfi-ol-3,l7-dione ll-nitrite, respectively.

B. 90: halogeno J8 nor D homo 4,13(17a)- androstarh'ene 11/3 ol 3,17 dione and 9a halogena- 18 nor D homo J,4,13(17a) ondrostatricne 11, 3- 0l-3,17-dioi1e.A solution of 9a-fiuoro-4-androstene-l1/9- ol-3,17-dioue ll-nitrite in toluene under a blanket of nitrogen is irradiated With a 200 watt mercury lamp in the manner of Example 1B. The resultant reaction mixture is filtered and the insoluble residue discarded. The filtrate is concentrated to a residue which is crystallized from acetone-hexane to give 9e-fiuoro-18-uor-D-homo- 4,13(17)-androstadiene-l 1fi-0l-3,17-di0ne.

Similarly, 9ot-cl1loro-4-androstene-1lfi-ol-3,l7-dione llnitrite, 9ot-bromo-4-androstene-llfi-ol-3,l7-dione ll-nitrite and 9a-fiuoro-1,4-androstadiene-l1fl-o1-3,l7-dione ll-nitrite in toluene are irradiated With a 200 Watt mercury lamp to give 9ot-chloro-l8-nor-D-horno-4,l3(17a)- androstadiene llfio1 3,17 dione, 9oz bromo 1 nor D homo 4,13(17a) androstadiene 11B ol 3, l7 dione and 9a fiuoro l8 nor D homo 1,4,13 (l7a)-androstatriene-l lfi-ol3,l7-dione, respectively.

EXAMPLE 4 4,6-androstodiene-1Idol-3,1 7-dz'one To a solution of 5 g. of 6-dehydrohydrocortisone (4,6-pregnadiene-l1/3,17a,21-triol-3,20-dione) in 300 ml. of 50% aqueous acetic acid is added 25 g. of sodium bismuthate. The mixture is stirred for 30 minutes at C., then filtered. The filtrate is diluted with water and extracted with methylene chloride. The organic extracts are combined and concentrated to a volume of about 25 ml. The concentrated solution is then filtered through a column of Florisil and eluted with ether. The eluates are combined and concentrated to a residue to give 4,5-androstadiene-l lB-ol-3,l7-dione.

In a similar manner, Su-l-prcgHene-llb,l7u,2l-triol- 3,20 dione, 7ot-methyl-4-pregnene-l1fi,17zx,2l-triol-3,20- dione, and 9ot-fiuoro-5u-1-pregnene-11B,17a,21-triol-3,20- dione are each reacted with sodium bismuthate in the above-described manner to give respectively l-androstene- 11,8-ol3,17-dione, 70c methyl 4-androstene-l 1,6-01-3,17- dione and 9u-fiuoro-l-androstene-llfiol-3,17-dione.

EXAMPLE 5 18nor-D-h0m0-4,6,13(17a) androstatrl'ene 1]-ol-3,Z 7-

dione, the 1 -del1ydr0 and the 9a-fluoro-1-dehydro analogs thereof A. In the manner described in Example 1A, 4,6-androstadiene-l1fi-ol-3,17-dione (prepared as described in Example 4), 1,4,6-androstatriene-llfl-ol-3,17-dione and 9afluoro-l,4-,6-androstatriene-l1fl-ol-3,17-dione are each reacted With nitrosyl chloride in pyridine and the resultant product isolated to give respectively, 4,6-androstadienc- 11fi-ol-3,17-dione ll-nitrite, 1,4,6-androstatriene-lIdol- 3,l7-dione -11-nitrite and 9e-fiuoro-1,4,6-androstatriene- 11,8-01-3, l7-dione ll-nitrite.

B. In the manner of Example 13, 4,6-androstadiene- 11/3-ol-3,17-dione ll-nitrite, 1,4,6-androstatriene-1l/i-ol- 3,17-dione ll-nitrite and 9a-fiuoro-1,4,6-androstatriene- 1lB-ol-3,l7-dione ll-nitrite are each irradiated with a 200 watt mercury lamp. The resultant products are isolated as described to give l8-nor-D-homo-4,6,l3(17a)- androstatriene 11B o1 3,17 dione, l8 nor D-homo- 1,4,6,-l3(17a)-androstatetraene-1lB-ol-3,17-dione and 9afluoro-lS-nor-D-horno l,4,6,13(l7a) androstatetraene- 11,8-01-3,17-dione.

EXAMPLE 6 18-nor-D-homo-L13 (17a) -androstadiene-1Jfi-ol- 3,1 7-dione l-Androstene-l1fi-ol-3,l7-dione (prepared as described in Example 4) is reacted With nitrosyl chloride in pyridine in the manner of Example 1A. The resultant product is isolated as described to give l-androstene-l1,B-ol-3,17- dione ll-nitrite.

In the manner of Example 1B, 21 toluene solution of l-androstene-l l ,8-ol-3,17-dione ll-nitrite is irradiated With a 200 Watt mercury lamp. The resultant product is isolated as described to give l8-nor-D-homo-l,l3(17a)- androstadiene-l lfi-ol-3,l7-dione.

1 '7 EXAMPLE 7 Derivatives of 18-n0r-D-hom0-4,13 (1 7a) -androstadiene- 11;9-0l-3,17-di0ne In the manner of Example 1A, 6tx-methyl-4-androstene-ll 3-o1-3,17-dione, 6a-fluoro-4-androstene-l 1B-o1-3, l7-dione, 6(3-fluoro-4-androstene-11fl-ol-3,17-dione, 6a-fluoro- 19-nor-4-androstene-1 15-01-3, 17-di0ne, out-fluoro-1,4-androstadiene-11B-o1-3,17-dione,

. 2a-methy1-4-androstene-1 1 p-ol-3, 17 -dione,

1 1a-rnethyl-4-androstene-1 1/3-ol-3 ,17-dione, 4-chloro-4-androstene-1 15-01-3 ,17-dione, 9a-flll010- 1 6a-acetoxy-4-androstene-1 1 18-01-3, 17-dione, and 7u-methyl-4-androstene-1 15-01-3, 17-dione are each reacted with nitrosyl chloride in pyridine. The resultant product is isolated togive,respectively. V 6a-methy1-4-aridrostene-1 15-01-3 17-dione 1 l-nitrite, 6a-fluoro 4-androstene-1 1,8-01-3, 17-dione 1 l-nitrite, 6B-fluoro-4-androstene-1 113-01-3, 17-dione 1 l-nitrite, 6a-fluoro-l9-nor-4 androstene-l 1,8-01-3, 17dione ll-nitrite, 6oc-fluoro-1,4-androstadiene-1 15-01-3, 17-dione 1 l-nitrite, 2u-methyl-4-androstene-1 15-01-3 ,17-dione 1 l-nitrite, 1 la-methyl-4-androstene-1 15-01-3, 17-dione 1 l-nitrite, 4-chloro-4-androstene-1 1 [3-01-3, 17 -dione 1 l-nitrite, 90c-fll1010- 1 6a-acetoxy-4-androstene-1 1,8-01-3, 17-di0ne ll-nitrite, and 7 a-methy1-4-androstene1 1fi-o1-3,17-dione 1 l-nitrite.

In the manner described in Example 1B, 6 a-methyl-4-andro stene-l 15-01-3 ,17-dione 1 l-nitrite, 6oa-flu0ro-4-androstene-1 lfl-o1-3,17-dione 1 l-nitn'te, 6 fi-fluoro-4-androstene-1 1 fl-ol-3,17-dione 1 l-nitrite, 6a-fluoro-19-nor-4-androstene-115-ol-3,17-dione ll-nitrite, j 6u-fluoro-1,4-androstadiene-116-01-3 ,17-dione ll-nitritc, 2a-methyl-4-androstene-1 1 ,8-01-3 ,17-dione, 1 l-nitrite, 1 1m-rnethyl-4-androstene-1 1,8-01-3, 17-dione 1 l-nitrite, 4-chloro-4-androstene-1 15-01-3, l7-dione 1 l-nitrite. 9oc-fiu010-1 6a-acetoxy-4-androstene-1 1 fl-ol-3, 17 -dione 1 l-nitrite, and 7oc-methyl-4-androstene-l 13-01-3, 17-dione 1 l-nitrite are each irradiated with a 200 watt mercury lamp and the resultant products isolated and purified to give respectively, fia-methyl-l 8-nor-D-homo-4, 1 3 17a) -androstadiene- 1 15-01-3, 17-dione, 6ot-fluoro-1 8-nor-D-homo-4,13 17 a) -androstadieue- 1118-01-3, 17-dione, 6fl-fluoro-18-nor-D-horno-4,l3 17a) -androstadiene- 116-01-3, 17-dione, j 6ot-fll101'0- 18,19-bis-nor-D-homo-4, 13 17 a) -androstadiene- 11 8-ol-3,17-dione, a-fluoro-l 8-nor-D-homo-1,4,13 17 a) -androstatriene- 1 1,8-01-3, l7-dione, 2a-methyl-18-nor-D-homo-4,13 17 a) -androstadiene- 1 113-01-3, 17-dione, V 1 1 a-methyl-l 8-nor-D-homo-4,13 17 a) -androstadiene- 1 1153-01-3 ,17-dione, 4-ch1oro-18-nor-D-homo-4,13 (17a)-androstadiene- 11B-ol-3,17-dione,

. 9a-fluoro-16a-acetoxy-18-nor-D-homo-4,13(17a)- androstadiene-l1}8-ol3,17-dione, and 7a-methyl-18-nor-D-homo-4, 13 (17a)-androstadiene- 1113-01-3 ,17-dione.

EXAMPLE 8 18n0r-D-h0m0-1,3,5 ('1l0),13(17t1) estratetraene 3,115-

dil-17-0ne 3-acylate and the 6a-fluor0 derivative thereof A. 18-n0r-D-hom0 1,3,5(),13(17a) estratetraene 3,11 B-dz'0l-17-0ne 3-acetate and the 6a-flu0r0 derivative there0f.A solution of 412 mg. of 11B hydroxyestrone 3-acetate in 7.5 ml. of pyridine is reacted with nitrosyl chloride according to the procedure of Example 1A. The resultant product is isolated and purified as described 13 to give llfl-hydroxyestrone 3-acetate ll-nitrite, M.P. 168171 C.

[011 (dioxane) H. 52 2.68 In (1,340) 275 m (61,200) \N11]O1 5.65, 5.72, 6.06, 6.20, 6.67, 8.30

A solution of 430 mg. of llfi-hydroxyestrone 3-acetate ll-nitrite in 200 ml. of benzene under a blanket of nitrogen is irradiated for onehour at 1820 C. with a 200 watt mercury lamp provided with a Pyrex filter. The reaction mixture is filtered and an insoluble residue discarded. The filtrate is evaporated in vacuo to a residue which is chromatographed on Florisil. The column is eluted with ether-hexane mixtures and those fractions eluted with 30-50% ether-in-hexane are combined. The combined fractions are concentrated to a residue which is crystallized from acetone-hexane to give 18-nor-D- homo- 1,3,5(1O),13 (17a)-estratetraene 3,1 lfl-diol-l7-one 3-acetate, M.P. 171-176 C.

mg 236 m (619,100) ANujol 2.95, 5.70, 5.97, 6.15 6.65, 8.05,.

In a similar manner, 6a-fluoro-1,3,5(10)-estartriene-3, 11,B- diol-17-one 3-acetate (prepared from the corresponding alcohol by the action of one equivalent of acetic anhydride in pyridine) is reacted with nitrosyl chloride in pyridine to give 6ot-fluoro-l,3,5(10)-estratriene-3,1lfi-diol- 17-one 3-acetate ll-nitrite which is irradiated with ultraviolet light to give 6a-fluor-o-18-nor-D-homo-1,3,5(10),13 (17a) estratetraene-3,1 1 fi-di-ol- 17-o11e 3-acetate.

B. 18 n0r-D-h0m0-1,3,5(10),13(17a)-estratetraene-3, 1Z/3-di0l-17-one 3-benzoate.The requisite intermediate, 1,3,5 (10)-estratriene-3,llfi-diol-17-one 3-benzoate, is prepared as follows:

200 mg. of llfi-hydroxyestrone (1,3,5 (lO)-estratriene- 3,11B-dicl-17-on-e) is dissolved in 3 ml. of pyridine containing mg. of benzoyl chloride. The reaction mixture is left at room temperature for 3 hours then poured into cold dilute hydrochloric acid. The aqueous mixture is stirred for 15 minutes. A solid precipitates which is filtered and crystallized from aqueous methanol to give 1,3,5 (lO)-estratriene-3,1lj3-diol-l7-one 3-benzoate.

In the manner of Example 1A, 1,3,5(10)-estratriene3, 11,8-diol-17-one 3-benzoate is reacted with nitrosyl chloride in pyridine and the resultant product isolated and purified to give 1,3,5(10)-estratriene-3,11,8-diol-17-one 3-benzoate ll-nitrite.

In the manner of Example 113, a toluene solution 0 1,3,5(lO)-estratriene-3,11fi-dio1-17-one 3 benzoate 11- nitrite is irradiated with a 200 watt mercury lamp. The resultant product is isolated as described to give 18-nor- D homo 1,3,5(10),13(17a)-estratetraene-3,11B-dio1-17- one 3-benzoate.

C. 18 n0r-D-h0m0-1,3,5 (10),13(17a)-estratetraene-3, 11B-dz'0l-17-0ne 3-l0wer alkan0ate.To a solution of 100 mg. of 1,3,5(10)-estr.atriene-3,11 fl-diol-17-one in 2 ml. of pyridine is added 100 mg. of icaprylic anhydride. The reaction mixture is allowed to stand at room temperature for 3 hours then is poured into cold dilute hydrochloric acid and stirred for 15 minutes. A solid separates which is filtered to give 1,3,5 (l0)-estratriene-3,11,8-diol-17-oue 3-caprylate.

In a similar manner, l,3,5(l0)-estratriene,3,1lfl-diol- 17-one is reacted with anhydrides of other lower alkanoic acids such as propionic anhydride and valeric anhydride ll 9 1,3,5(10) estratriene 3,11,8-diol-7-one 3-caprylate 11- nitrite.

In the manner described in Example 113, the 3-alkanoyloxy ll-nitrite estratriene esters prepared above are eachirra-diated in a toluene solution with a 200 watt mercury lamp. The respective products are isolated as described to give 18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,11B-diol-17-one 3-propionate, 18-nor-D-l1omo- 1,3,5(10),13(l7a)-estratetraene-3, 11/3-diol-17-one 3-valerate, and 18-nor-D-homo- 1 ,3,5 10) ,13 (17a -estratetraone-3,11B-diol-l7-one 3-capryloate, respectively.

EXAMPLE 9 18-n0r-D-h0m0-1,3,5(10) ,13 (1 7a) -estratetraene- 3,115-diol-17-one 18 nor D homo-1,3,5(10),13(17a)-estratetraene-3, 1lfl-diol-17-one 3-acetate (the compound of Example 8A) is subjected to the action of a culture of Flavobacterium dehydrogenans (Rutgers Collection No. 130) as follows:

The culture of the organism is prepared by propagating it in a nutrient agar medium at 30 C. for 24 to 72 hours. During incubation, the inoculated tube is exposed to light with the resultant development of a yellow pigment characteristic of the species. The developed culture is rinsed from an agar slant under sterile conditions into a sterile medium of pH 6.8 and having the following composition:

Gm. Yeast extract (Difco) 10 Potassium phosphate monobasic 4.48 Sodium phosphate dibasic 4.68

Tap water, to 1 liter.

This culture medium has previously been autoclaved, at 15 lb. pressure, for twenty minutes to obtain aseptic conditions, and cooled. The variant is grown in the medium under constant illumination, using the visible range of the spectrum. The incubation temperature is maintained at about 33 C. and is conducted under aerobic conditions. Aeration is accomplished by agitation and/ or blowing air through the culture medium.

After the organism has grown for 12 to 24 hours (or longer, if desired), 100 ml. of the growing culture are introduced into each of ten flasks, and to each flask are added 200 mg. of 18nor-D-homo-1,3,5(10),13(17a)- estratetraene-3,11fl-diol-17-one 3-acetate dissolved in a minimum volume of ethanol. The reaction mixtures are then shaken at 30 C. for 12 to 72 hours. The reaction is stopped when paper chromatography indicates that there is no more starting material.

The contents of the flasks are combined and extracted with methylene chloride. The extracts are concentrated and the residue is crystallized from acetone-hexane yielding 18 nor D-homo-1,3,5(l),13(17a)-estratetraene-3, 11,6-diol-17-0ne.

EXAMPLE 18-n0r-D-lz0m0-1,3,5 (10) ,13 (1 7a)-eszratetraene-3,11- diol-Z 7-0ne 3-[0wer alkyl ether watt mercury lamp in the manner of Example 1B. The

resultant product is isolated and purified as described to give 18 nor-D-homo-1,3,5 10) ,13 l7a)-estratetraene-3, 11B-diol-l7-one 3-methylether.

B. 18 n0r-D-h0m0-1,3,5 (10 ,13 (17a) -estratetraene-3, 11,8-di0l-17-0ne 3-ethylether.The requisite intermediate, 1,3,5 10) estratriene-3,11B-diol-17-one 3-ethylether, is

prepared in the following manner.

To 1 g. of 1,3,5(10)-estratriene-3,11B-diol-l7-one in 30 ml. of 10% ethanolic potassium hydroxide solution is added 3 ml. of diethyl sulfate over a two hour period (0.5 ml. portions every 20 minutes). The reaction mixture is stirred for minutes, then diluted with ml. of water. A Solid results which is filtered, Washed with Water and dried to give 3-ethoxy-l,3,5(10)-estratriene-1113-01-17- one.

In the manner of Example 1A, l,3,5(10)-estratriene- 3,11,6-diol-17-one 3-ethylether is reacted with nitrosyl chloride in pyridine and the resultant product isolated and purified to give 1,3,5(10)-estratriene-3,11/3-diol-17- one 3-ethylether ll-nitrite which is then irradiated with a 200 watt mercury lamp in the manner of Example 13 to give l8-nor-D-homo-1,3,5( 10) ,13 17a) -estratetraene- 3,1 1,8-diol-17-one 3-ethylether.

EXAMPLE 1 1 16-hal0geno-18-n0r-D-homo 4,13(17a) androstadiene- 11B-0l-3,17-di0ne and 9u,16-di/zal0gen0 18 nor-D- h0m0-4,13 (1 7a)-androstadiene-1 1,8-0l-3,1 7-clz'0ne A. 16 halogeno 4 androstene 11,8 ol 3,17 dione 1 1 -nizrite and 9a,] 6-dihal0gen0-4-androstene-1Iii-ol- 3,17-di0ne 11-nitrzte.A solution of 16B-fluoro-4-androstene-l1p-ol-3,17-dione in pyridine is reacted with nitrosyl chloride at 30 C. to 10 C. according to the procedure of Example 1A. The resultant product is isolated and purified in the described manner to give 16,8-fiuoro-4- androstene-l 1fi-ol-3,17-dione ll-nitrite.

In a similar manner 9a,16/3-difiuoro-4-androstene-11fi-ol-3 ,17-dione, 9oz,16ot-dlllllOIO-4-E1Ildl08l6fi6-l l fl-ol-3 ,17-dione, 9a-chloro-16/i-fluoro-4-androstene-1 1fl-ol-3 ,17-dione, 9a-chloro-16a-fiuoro-4-androstene-11fl-ol-3,l7-dione, 9a-fiuoro-16fl-chloro-4-androstene-1 l fi-ol-3,17-dione and 9a,16,8-dichloro-4-androster1e-11,8-01-3 ,17-dione are reacted with nitrosyl chloride in pyridine to give, respectively, 9u,1ofi-difiuoro-4-androstene-11fi-ol-3,17-dione ll-nitrite, 9a,16a-difluoro-4-androstene-11,8-ol-3,7-dione 1 l-nitrite, 9a-chloro-16/3-fluoro-4-androstene-l1,8-ol-3,l7-dione 11- nitrite, 9a-chloro-16a-fluoro-4-androstene-11fl-ol-3,17-dione 11- nitrite, 9a-fiuoro-16B-chloro-4-androstene-1lfl-ol-3,17-dione 11- nitrite, and 9a,16,8-dichloro-4-androstene-l1fi-ol-3,17-dione ll-nitrite.

B. 16 halogeno 18 nor D homo 4,13(17a) androstadiene 11,8 ol 3,17 dione and 9a,]6 dihalogeno 18 nor D homo 4,13(17a) androstadfene- 11fl-0l-3,17-di0ne.-A solution of 16/3-fluoro-4-androstene-l1[3-ol-3,17-dione ll-ru'trite in toluene, under a blanket of nitrogen, is irradiated with a 200 watt mercury lamp in the manner of Example 1B. The resultant reaction mixture is filtered and the insoluble residue discarded. The filtrate is concentrated to a residue which is crystallized from acetone-hexane to give 16,8-fluoro-18-nor-D- homo-4,13(17a)-androstadiene-11/3-ol-3,l7-dione.

Similarly, following the above procedure, each of the ll-nitrite esters prepared in Example 11A second paragraph is utilized as starting compound in place of fiuoro-4-androstene-l1B-ol-3,17-dione ll-nitrite and there is obtained, respectively, 90:,1613-(lifll1010-l8-I1Ol'Dh0m0+4,13 (17a)-androstadiene-l1,8-ol-3,17-dione, 9u-chloro-16/3-fluoro-18-nor-D-homo-4,l3(l7a)-androstadiene-l1fi-ol-3,l7-dione, 9oc-ChlO1O-16oc-flUOIO-l 8-nor-D-homo-4,13 l7a)-androstadiene-l1fi-ol-3,17-dione, 9.x-fluoro-16,6-chloro-18-nor-D-homo-4,13 l7a)-androstadiene-l1,8-ol-3,17-dione and 9a,16/3-dichloro-18-nor-D-homo-4, 1 3( 17a) -androstadiene-l lfl-ol-3,17-dione.

21 EXAMPLE 12 90cuoro-16a-methyl-18-nor-D-homo-1,4,13 (1 7a) androstatriene-I Idol-3,1 7 -dione A. 90: fluoro 16oz methyl 1,4 androstadicne 11 3- ol 3,17 dione.--9a fluoro 16a methyl 1,4 pregnadiene-11fi,l7 a,21-triol-3,20-dine is reacted with sodium bismuthate and 50. percent aqueous acetic acid in a manner similar to that described in Example 4. The resultant product is isolated and purified to give 9u-fiuoro- 16cc methyl 1,4 androstadiene 11B ol 3,17 dione, M.P. 226-233 C. (dec.).

B. 9 fluoro 16a methyl 1,4 androstadiene 11,8- 0l-3,1 7-dione 1l-nitrite.9a-fluoro-l6u-methyl-1,4-androstadiene-l1/3-ol-3,17-dione is reacted with nitrosyl chloride in pyridine according to the procedure of Example 1A and the resultant product isolated and purified to give 9a-flll010- 1 6a-rnethyl-1,4-androstadiene-1 15-01-3, 17-

dione ll-nitrite,

melting point 213-217 C.; N 236 111, (615,400); [04D +135 (CHCl MNujol C. 90: fluoro 16oz methyl l8 nor D homo 1,4,13(17a) androstatriene 11,8 ol 3,17 dione.- 9m fluoro 16a methyl 1,4 androstadiene 11,6 ol- 3,17-dione ll-nitrite dissolved in toluene is irradiated under nitrogen with ultraviolet light according to the procedure of Example 1B. The irradiated solution is cooled, filtered, and the insoluble residue discarded. The remaining filtrate is evaporated in vacuo to a residue which is crystallized from aqueous acetone to give 9ot-fiuoro- 16a methyl 18 nor D homo 1,4,13(17a) androstatriene-l1fi-0l-3,17-dione, melting point 265-268 C.;

A122 242 m (633,000); [a] +102 (pyr); MNujol Similarly, when 16a-methyl-1,4-pregnadiene-1113,170, 21-triol-3,20-dione is reacted according to procedures 12A-C there is obtained 16a-methyl-18-nor-D-homo- .1,4,13 (17a) -androstatriene 11fi-ol-3,17-dione.

EXAMPLE 13 Preparation of JJB-hydroxy-I 7- keto-androstanes from the corresponding 11fl,17a,21-trihydroxy 20 keto-pregnanes A. To a solution of 1 gram of 60,l6oc-dl1116tl1Yl-9zxfluoro1,4-pregnadiene-11/3,l7a,21-triol-3,20-dione Zl-acetate in 40 ml. of methanol is added 1 ml. of 70 percent aqueous perchloric acid. The reaction solution is stirred at room temperature overnight then poured into water, a precipitate separates which is filtered and dried to give 611,160: dirnethyl 9a fluoro 1,4 pregnadiene 11,8,- 17a,2l-triol-3,20-dione.

In a similar manner 6a,16a-dirnethyl-4-pregene-1 1 8,17u,2l-triol-3,20-dione 2l-acetate,

6a-fluoro-9ot-chlorol 6a-methyl-4-pregnenel 1 B, 170:,2 1- triol-3,20-dione ZI-acetate,

6a-fiuoro-9e-bromol 6vt-methyl-4-pregnene-l 1,8, 170:,2 l-

triol-3,20-dione 21-acetate,

2oc-methyl-4,6-pregnadiene-1 1,8, 17cc,21-ll1lOl3,20-di0n 21-acetate,

2a-methyl-9u-iodo-4,6-pregnadiene-1 l5, 170:,21-tfiOl-3 ,20-

dione 2l-acetate, and

2a-methyl9a-bromo-4,6-pregnadiene-l 15,17a-21-triol- 3,20-dione ZI-acetate are each reacted with aqueous per-chloric acid to yield respectively 6a,16a-dirnethyl-4-pregnene-1 1,8, 171 2 1 -triol-3,20-di.one,

22 6wflu0IO-9oc-Cl1l010- 1 6a-methyl-4-pregnene-l 13, l 7oc,2 1-

triol-3,20-dione, 6a-fluoro-9u-bromo-16a-methyl-4-pregnene-l 1B,17a,2l-

triol-3 ,20-dione, 2a-methyl-4,6-pregnadiene-1 1B,17a,21-triol-3,20-dione, 2wmethyl-9u-iodo-4,6-pregnadiene-1 1 ,8, 17 oc,2l-l1iOl-3,20-

dione, and 2a-methyl-9u-bromo-4,6-pregnadiene-1 1 3,l7u,21-triol- 3 ,20-dione.

B. A solution of 6a,16oc-dimethyl9a-fluoro-1,4-pregnadiene-l1,8,17u,2l-triol-3,20-dione in 50 percent aqueous acetic acid is reacted with sodium bismuthate in the manner described in Example 4 and the resultant product isolated and purified to give 6a,16a-dimethyl-9a-fiuoro-L4- androstadiene-l 1 [3-01-3, 17-dione.

In a similar manner,

are each reacted with sodiumbismuthate in the manner of Example 4 to give respectively,

6a,16a-dimethyl-4-androstene-1 1 3-01-3 ,17-dione,

6a-fluoro-9a-ch1oro-16a-methy1-4-androstene-1 1,8-01-3 ,17-

dione,

6a-fluoro-9a-bromo-l6u-methyl-4-androstene-1 15-01-3, 17

dione,

2a-rnethyl-4,6-androstadiene-1 1 5-018 ,l7-dione,

2a-methyl-9a-iodo-4,6-androstadiene-1 1,8-01-3 ,17-dione,

2ot-methyl-9 ot-bromo-4,6-androstadiene-l 1,8-01-3, 17-dione,

9a,16B-difiuoro-1,4-androstadiene-l 1,8-01-3 ,17-dione,

9a-bromo-16,8-fluoro-4-androstene-1 1 fi-ol-B ,17-dione,

:,1 a-dimethyl-1,4-androstadiene-1 1fl-ol-3,1'7-dione,

Zea-methyl-9u-fluoro-4,6-androstadiene-1 15-01-3 l7-dione,

9m-fluoro-1-androstene-1 15-01-3 ,17-dione,

2a-ethyl-9a-chloro-4,6-androstadiene-1 113-01-3, 17-dione.

EXAMPLE 14 6,16 disubstituted 18 nor D homo 4,13(J7a)- androstadiene-11B-ol-3J7-diones and 6,16-disubstz'tuted- J8 nor D homo 1,4,13(17a) androstatriene-ILB- 0l-3,17-diones A. In the manner described in Example 1A 6u,16a-dimethyl 9a fluoro 1,4 androstadiene 11B ol 3,17- dione is reacted with nitrosyl chloride in pyridine and the resultant product isolated to give 6a,16a dimethyl 9afiuoro-1,4-androstadiene-1 1fl-ol-3,l7-dione 1 1-nitrite.

In the manner of Example 1B, 6a,16a-dimethy1-9afluoro-1,4-androstadiene-11fl-o1-3,17-dione 11 -nitrite in 25 combined organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo to a residue having a volume of 1-2 ml.

The ethylene dichloride residue is then placed on a chromatographic column consisting of silica gel, mixed with a small volume of methylene chloride. The column is developed with methylene chloride and the eluates are combined and concentrated in vacuo to a residue which is crystallized from acetone-hexane to give 16tx-br-omo-4- androstene-1 1151-01-3, 17-dione.

In a similar manner l6,8-bromo-4-androstene-3,l7-dione, 16a-chloro-4-androstene-3,-17-dione, and 16,8-chloro- 4-androstene-3,l7-dione are each subjected to the action of Curvularia lunata and each of the resultant products isolated and purified to give, respectively, 16B-bromo-4- androstene 11 ol 3,17 dione, 16oz chloro 4- androstene-l1fi-ol-3,17-dione, and l65-chloro-4-androstene-l l ,6-ol-3 ,17-dione.

B. 16 Imrlogeno 4 androstene 11,6 ol 3,17 dione 11-nitrite.-16a bromo 4 androstene 11B ol 3,17- dione and l6/3-bromo-4-androstene-1 lB-ol-3,17-dione, 160cchloro-4-androstene-1lB-ol-3, 17-dione, and 16,6-chlo-ro-4- androstene-llB-ol-3,17-dione, are each reacted with nitrosyl chloride according to the procedure of Example lA. Isolation of the resultant products yields, respectively, 16a bromo 4 androstene 11B ol 3,17 dione I l-nitrite and 16B-bromo-4androstene'l1,6-ol-3,17-dione l l-nitrite, 16ot-chloro-4-androstene-1lfl-ol-3,l7-dione 11- nitrite and 16,8-chloro-4-androstene-llfi-ol-3,l7-dione 11lnitrite.

C. 16-hzzl0geno-18-nor D-homo 4,13(17a) androstadiene-l Idol-3,1 7-di0ne.16a-brorn0 4 androstene-l 1,8- ol-3,17-dione ll-nitrite and 16B-bromo-4-androstene-l1B- ol-3,17-dione ll-nitrite, l6ot-chloro-4-androstene-115-01 3,17-dione ll-nitrite and 16,8-chloro-4-androstene-l1,8-01- 3,l7-di-one 11-nitrite are each irradiated with a 200 Watt mercury lamp in a toluene solution while under a blanket of nitrogen according to the procedure of Example 1B. The resultant products are isolated and purified to give, respectively, 16a-bromo-18-nor-D-homo 4,13(l7a) androstadiene-llB-ol-3,17-dione and l6/3-bromo-18-nor-D- homo-4,13(17a)-androstadiene-l1p-ol 3,17 dione, 160cchloro-18-nor-D-homo-4,13( 17a) androstadiene 11,8 ol- 3,17-dione, and 16B-chloro-18-nonD homo 4,13 (17a)- androstadiene-l 118-01-3, 17-dione.

EXAMPLE 19 -androstene-3;3,l 1 B-diol-I 7-one Fresh hog or beef adrenal glands are passed through a meat grinder, then 250 parts by weight of the ground adrenals are stirred with 750 parts of a solution prepared by mixing together 40 parts of a 4.5 percent solution of sodium chloride plus 1.6 parts of a 5.75 percent solution of potassium chloride plus 0.4 part of a 19.1 solution of magnesium sulphate, plus 20 parts of an 0.1 molar phosphate buffer of pH 7.4 plus 30 parts of an 0.15 molar solution of sodium fumarate or sodium citrate and 110 parts of water. This solution has a pH of about 7.4 and is at a temperature of 37 C. when added to the adrenal tissue. To this mixture is added, with stirring, one part of S-androstene-Bfi-ol-17-one dissolved in 30 parts of propylene glycol at 37 C. The final mixture is incubated at 37 C. for 2 hours with vigorous stirring and then is extracted with chloroform. The chloroform extracts are combined and concentrated to a small volume and then placed on a Florisil column, dampened with hexane, and eluted with hexane-ether, ether, and ether-acetone and acetone. The like fractions are combined and concentrated to a residue of substantially S-androstene-BB-llfidiol-l7-one.

In a similar manner 5-androstene-3t3-l6a-diol-l7-one is A solution of 10 g. of 5-pregnene-3B,l7a,21-triol-11,20- dione in ml. of tetrahydrofuran is added dropwise over a 30 minute period to a solution of 400 g. of lithium aluminum hydride in 300 ml. of distilled tetrahydrofuran cooled in an ice bath. When the addition is complete, the stirred reaction mixture is warmed to reflux temperature then refluxed for two hours. The reaction mixture is then cooled and 100 ml. of ethyl acetate added dropwise, followed by 100 ml. of saturated aqueous sodium sulfate. The mixture is filtered and the filtrate dried over magnesium sulfate, concentrated in vacuo to a residue which is triturated with ether and filtered to give S-pregnone-35,1lB,17o,20,21-pentol.

A solution of 5 grams of S-pregnene-BBJl5,17a,20,21- pentol in 300 ml. of 50 percent aqueous acetic acid is reacted With 25 g. of sodium bismuthate in the manner of Example 4. The resultant product is isolated and puritied in a manner similar to that described to give, S-androstem-35,1lfi-diol-l7-one.

XAMPLE 20 16-halogeno-5=androstene-3B,1JB-diol-I7-0ne A solution of 1ct-brorno-5-androstene-3p-ol-17-one in propylene glycol is reacted with hog or beef adrenals according to the procedure of Example 19A. The resultant product is isolated in the described manner to give, 16a-bromo-5-androstene-3B,1lfl-diol-l7-one.

In a similar manner, 16fi-bromo-5-androstene-3 3-01-17- one, 16a-chloro-5-androstene-3B ol 17 one, and 16B- chloro-S-androstene-S 8-ol-17-one are reacted with hog or beef adrenals and the resultant product isolated to give, respectively, 16p -brorno-5-androstene-3B,llfl diol-17-one, 16u-chloro-5-androstene-3t9,ll5 diol l7 one and 16,8- chloro-5-androstene-3fl,11e-diol-17-one.

EXAMPLE 21 S ot-halogerzo-Landrostene313,]1{3-di0l-17-0ne 3-acetate and 16-substituled derivatives thereof A. S-anarostene-SfiJJB-dioZ-U-one 3 acetate.-5-androstene-3[3,1lfi-diol-l7-one is reacted with acetic anhydride in pyridine in the manner described in Example 8C. The resultant product is isolated as described to give 5-androstene-3,8,llfi-diol-l7-one 3-acetate.

In a similar manner, 5-androstene-3B,1113,16a-triol-l7- one, 16a-bromo-5-androstene-3B,1lfi-diol 17 one, 165- bromo-5-androstene-3B,l1,8-diol-17-one, z-Chl01'0-5-3I1- drostene-3fi,l1,8-diol17one, and 166 chloro 5 androstene-3,8,l1[3-diol-17-one are each reacted with acetic anhydride in pyridine to give, respectively, S-androstene- 3/3,1l/3,16a-triol-17-one 3-16-diacetate, 160t-bIOIT10-5-a1'1- drostene-3,8,1lfi-diol-llone 3-acetate, 16B-bromo-5-androstene-3,9,1 1,8-diol-17-ene 3-acetate, l6a-chloro 5 androstene-3fi,llfl-diol-17-one 3 acetate, and 16fl-chloro-5- androstene-3,8,1 1 fi-diol-l7-one 3-acetate.

B. 5,9(11)-andr0stadiene-Sfi-ol-Z7-0ne 3 acetate.A solution of 5 g. of 5-androstene-3B,llfi-diol-17-one 3-acetate in 100 ml. of pyridine is chilled to 0 C. and a solution of 10 ml. of methanesulfonyl chloride in 20 ml. of chloroform is added dropwise. The mixture is allowed to stand in the ice box for 100 hours, then a little ice is added and the solution diluted with chloroform. The organic solution is washed with water, 5 percent hydrochloric acid, 5 percent aqueous sodium bicarbonate, and again with water. The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to a residue which is crystallized from acetone-hexane to give 5,9(11)- androstadiene-3B-ol-l7-one 3-acetate.

In a similar manner S-androstene-BBJ113,16a-triol-17- one 3,16-diacetate, l6a-bromo-5-androstene-35,l1,8-di0l l7-one 3-acetate, l6fi-bromo-5-androstene-3fi,l1 fi-diol-17- one 3-acetate, 16a-chloro-5-androstene-3fi,11p-diol-17-one S-acetate, and lops-chloro-5-androstene-3e,l1,6 diol 17- one B-acetate are each reacted with methanesulfonyl chloride in the manner described above and the resultant 27 product isolated to give, respectively, 5,9(11)-androstadiene-35,16u-diol-17-one, 3,16-diacetate, 16OL-bI'OlT10-5,9- (11)-androstadiene-35-ol-17-one 3-aceta'te, 165-brorno-5, 9(11)-androstadiene-35-ol-17-one 3-acetate, 16wchloro- 5,9(11)-androstadiene-35-ol-17-one 3-acetate, and 165- chloro-5,9( 11 )-androstadiene-35-ol-17-one 3-acetate.

C. 9a-br0m0-5-andr0stene-35,115-di0l 17 one 3-acetate.-To a solution of 0.155 g. of 5,9(11)-androstadiene- 35-ol-17-one 3-acetate in 20 ml. of dioxane (which has been purified by refluxing over sodium followed by distillation) and 2 ml. of water is added 0.07 g. of N-bromoacetamide and 1 ml. of 1.5 N perchloric acid. The mixture is allowed to stand for 2 hours, then a solution of 0.2 g. of sodium sulfite in 2 ml. of water is added and the mixture extracted with methylene chloride. The organic extracts are combined, washed with water, dried over magnesium sulfate and evaporated to a residue which is crystallized from acetone to give, 9oibromo-5-androstene- 35,115-diol-17-one 3-acetate.

In a similar manner 5,9(11)-androstadiene-35,16a-dio1- 17-one diacetate, 16rx-br0m0-5,9(11)-androstadiene-35- ol-17-one 3-acetate, 165-bromo-5,9(11)-androstadiene-35- ol-17-one 3-acetate, 16e-chloro-5,9(11)-androstadiene- 35-ol-17-one 3-acetate, and 165-chloro-5,9(11)-androstadiene-35-ol-17-one S-acetate are each reacted with N- bromoacetamide and perchloric acid to yield respectively, 9oi-bromo-5-androstene-35,115,16oi-triol-17-one 3,16 diacetate, 9a,16ix-dibromo-5-androstene-35,115-diol-l7-0ne 3-acetate, 90;,165 dibromo-S-androstene-35-115-diol-17- one 3-acetate, 9a-brorno-16a-chloro-5-androstene-35,115- diol-17-one 3-acetate, 9a-bromo-165-chloro-5-androstene 3 5,1 15-dioll7-one 3-acetate.

D. 95,115-xido-5-ana'r0stene-35-0l-17-0ne 3-acetate.-- To 0.150 g. of 9a-bromo-5-androstene-35,115-diol-17-one 3-acetate in 30 ml. of acetone is added 0.3 g. of potassium acetate. The reaction mixture is refluxed for 6 hours then the acetone is distilled, water is added to the resultant residue. A solid separates which is filtered and crystallized from methanol-water to give, 95,115-oxido-5-androstene-35-ol-17-one 3-acetate.

In a similar manner 9a-bromo-5-androstene-35,115, 16OL-triO1' 17 -one 3 ,16-diacetate, 906,160L-dib1'011'105-3I1df0- stene-35,115-diol-17-one 3-acetate, 9a,165-dibromo-5-androstene-35,115-diol-17-one 3-acetate, 90 bromo-16uchloro-5-androstene-35,115-diol-17-one 3-acetate, and 90sbromo-l6a-chloro-5-androstene-3at,1 15-diol-17-one 3-acetate are each reacted with potassium acetate in acetone to give respectively, 95,115-oxido-5-androstene-35,16u-diol- 17-one 3,16-diacetate, 95,115-oxido-16a-bromo-5-androstene-35-ol-17-one 3-acetate, 95,115-oxido-165-bromo-5- androstene-35-ol-17-o-ne S-acetate, 95,115-oxido-16a-chloro-5-androstene-35-ol-17-one 3-acetate, and 95,115-oxido- 165-chloro-5-androstene-35-ol-17-one S-acetate.

E. 9a-flu0r0-5-andr0stene-55-115-di0l-17-0ne 3 acetate.To 3.5 g. of hydrogen fluoride in 20 ml. of chloroform and 0.6 m1. of tetrahydrofuran at -10 C. is added one g. of 95,115-oxido5-androstene-35-ol-17-one 3-acetate. The reaction mixture is kept at 10 C. for 3 hours then poured into aqueous sodium carbonate solution. The organic solvent layer is separated from the Water and evaporated to a residue which is crystallized from methanol to give, 9a-fluoro-5-androstene35,115-diol-17-one 3-acetate.

In a similar manner, 95,115-oxido-5-androstene-35,16adiol-17-one diacetate, 95,115-oxido-16a-bromo-5-androstene-35-ol-17-one S-acetate, 95,115-oxido-165-bromo-5- androstene-35-ol-17-one 3-acetate, 95,115 oxide-160ichloro-5-androstene-35-01-17-one 3-acetate, and 95,115- oxido-165-chloro-5-androstene-35-01-17-one B-acetate are each reacted with hydrogen fluoride in chloroform and tetrahydrofuran in the manner described above to give, respectively, 9a fiuoro-5-androstene-35,115,16a-triol-17- one 3,-16diacetate, 9oc-fiu010 16a bromo-S-androstene- 35,115-di0l-17-one 3-acetate, 9ct-fluoro-165-bromo6- androstene 35,115-diol-17-0ne 3-acetate, 90L-fil-101O-161X- 25:3 chloro-5-androstene-35,1l5-diol-17-one 3-acetate, and 91xfluoro 165 chloro-5-androstene-35,l15-diol-17-one 3- acetate.

F. Que-chl0r0-5-aizdr0stene- 35,115-di0l-17-0ne 3-acetate.-A solution of one g. of 95,115-oxido-5-androstene- 35-0l-17-0ne 3-acetate in 30 m1. of alcohol-free chloroform is saturated at 0 C. with anhydrous hydrogen chloride and the mixture allowed to stand at 0 C. for 6 hours. The solvent is distilled in vacuo from the reaction mixture leaving a residue which is crystallized from acetone to give 9rx-chloro-5-androstene-35,115-diol-17-one 3- acetate.

In a similar manner, 95, 15-oxido-5-androstene-35,16adiol-17-0ne diacetate, 95,115-oxido-16a-bromo-5-androstene-35-ol-l7-one S-acetate, 95,115-oxid0-165-bromo-5- androstene-35-ol-17-one 3-acetate, 95,115-oxido 16ozchloro-5-androstene-35-01-17-one 3-acetate, and 95,115- oxido-165-chloro-5-androstene-3 5-01-17-one 3-acetate, are each reacted with anhydrous hydrogen chloride in chloroform to give, respectively, 9oi-chloro-5-androstene-35,115, 16a-triol-17-one 3,16-diacetate, 9oc-Chl01O-l6oL-bIOfHO-5- androstene-35,115-diol-17-one 3-acetate, 9a-chloro-165- bron1o-5androstene-35,115-diol-17-one S-acetate, ,16udichloro-S-androstene-35,115-dio1-17-one 3-acetate, and 9a,165-dichloro-5-androstene-35,115-diol-17-one 3 acetate.

EXAMPLE 22 18-n0r-D-h0m0-5,13(17a) androstadiene 35,11 5-di0l- 17-0ne 3-acetate, lo-substituted derivatives thereof and their 9a-hal0gen0 derivatives A. l8-ntor-D-homo-5J3 (17a) andr0stadiene-35,1l 5- -diol-17-0ne 3-acetate.--In a manner similar to that described in Example 1A 5-androstene-35,115-dio1-17-one 3-acetate (the compound of Example 21) is reacted with nitrosyl chloride in pyridine and the resultant product isolated to give 5-androstene-35,115-diol-17-0ne 3-acetate ll-nitrite.

By utilizing the procedure similar to that described in Example 1B 5-androstene-35,115-dio1-17-one 3-acetate ll-nitrite in toluene i s irradiated with a 200 Watt mercury lamp and the resultant product isolated and purified to give 18-nor-D-homo-5,13(17a)-androstadione-35,115-diol-17-one 3-acetate.

B. In a similar measure manner to that described in Experiment 22A,

5-androstene-35,1 1,8,16a-t1i0l-17-0I1G 3,16-diacetate,

16oc=brom0-5-androstenc-35,115-di0l-17-one 3-acetate,

-bromo-5-androstene-35,115-diol-17-one 3-acetate,

16a-chloro-5-androstene-35,115-diol-17-one B-acetate,

165-chloro-5-androstene-35,115-diol-17-one 3-acetate,

9u-fluOro-S-andmstene-35,115-diol-17-one 3-acetate,

9a-chloro-5-androstenc-35,115-diol-17-one 3-acetate,

9oi-fluoro-5-androstene-35,115,16a-triol-17-0ne 3,16-diacetate,

9a-chloro-5 -androstene-3 5,1 15,16a-triol-17-one 3,16-

diacetate,

90c-b1011105 -androstene-3 5, 1 1 5, 1 60c-I1Ii0l- 17-one 3-16-diacetate,

9oa-f1uoro-16u-bromo-5-andr0st6ne-35,115-di0l-17-one 3- acetate,

9a-Chl0101 6a-bromo-5 -androstene-3 5,1 15-dio1-17-one 3-acetate,

9a,16a-dibromo-5-androstene-35,1 15-diol-17-one 3-acetate,

9a-fluoro-165-bromo-S-androstene-35,115-diol-17-one 3- acetate,

9a,165-dibromo-5-androstene-35,115-diol-17-one 3-acetate,

9a-fluoro-16a-chloro-S-androstene-35,115-diol-17-one 3-acetate,

31 for 15 minutes. A solid separates which is filtered and dried to give 16,6-methyl-1,3,5(10)-estratriene-3,11fi-di0l 17-one 3-acetate.

In a similar manner, 16,8-bromo-1,3,5(10)-estratriene- 3,r1lfl-diol-17-one,6fl-methyl 1,3,5(1O)-estratriene-3,11 8- diol 17 one, 6-methyl-1,3,5(10),6-estratetraene-3,11B- diol-17-one, and 1,3,5 10)-estratriene-3,1 1,8, 1 61x-triol-17- one are each reacted with acetic anhydride in pyridine to give respectively 16,8-bromo1,3,5(10)-estratriene-3,l1fldiol-17-one 3-acetate, 6,8-methyl-1,3,5(10)-estratriene-3, 11/3-diol-17-one 3-acetate, 6-methyl-1,3,5(10),6-estratetracue-3,11fl-diol-17-one 3-acetate and 1,3,5(1())-estratriene- 3,11,13,16oc-t1i01 3,16-diacetate.

C. II-nitrite esters of 1,3,5 (10)-estratrienes and 19-n0r- 4-androstenes.-3 methoxy-16B-methyl-1,3,5(10)-estratriene-11,8-ol-17-one in pyridine is reacted with nitrosyl chloride in a manner similar to that described in Example 1A. The resultant product is isolated as described to give 3-methoxy-16fl-methyl 1,3,5(10) estratriene 113 ol- 17-one ll-nitrite.

In a similar manner the llfl-hydroxy estratrienes and 19-nor-4-androstenes prepared as described in Example 23A and protectively esterified as shown in Example 23B are each reacted with nitrosyl chloride in pyridine to yield respectively 16/3-methyl-1,3,5(10)-estratriene 3 ,1 lfi-diol- 17-one 3-acetate I l-nitrite, 16B-br0mo-1,3,5(10)-estratriene 3,1 1[3-diol-17-one 3-acetate ll-nitrite, 16abr0mo-1,3,5 (l)-est-ratriene-3,11(3-diol-17-one 3-acctate 11-nitrite, 6,6- methyl1,3,5(10)-estratriene-3,11/3-diol-17-0ne 3 acetate ll-nitrite, 6 methyl-1,3,5(10),6-estratetraene-3,1lfi-diol- 17-one 3-acetate ll-nit-rite, 1,3,5(10) estratriene 3,1113, 16a-trio1-17-one 3,16-diacetate ll-nitrite, 6,8-fluoro-19-nor- 4-androstene-11-ol-3,17-dione 11-nitrite and 16fi-1nethyl- 19-nor-4-androstene-11B-ol-3,17-dione ll-nitrite.

D. Photolysis 0 the ll-nitrite esters of 1,3,5(10)-estratrienes and l 9-n0r-4andr0stenes.3-methoxy-16 8-methyl-1,3,5 (10)-estratriene-11/8-ol-17-one 11-nitrite in benzene under a blanket of nitrogen is irradiated with a 200 watt mercury lamp provided with a Pyrex filter in a manner described in Example 8A. The resultant product is isolated in a manner similar to that described in Example 8A to give S-methoxy-l 65-methyl-18-nor-D-'homo-1,3,5

(10) ,13 17a) -estratetraene-1 1 fl-ol-17-one.

Similarly, the ll-nitrite ester intermediates prepared as described in Example 23C are each irradiated with ultraviolet light and isolated to give respectively E. Hydrolysis of any ester groups present.16,B-methyl-18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,115- diol-17-one S-acetate, 16/3-bromo-18-nor-D-homo-1,3,5 (10),13(l7a)-estratetraene-3,1lfi-diol 17 one 3-acetate, 16u-brom0-18-nor-D-homo 1,3,5(10),13(17a) estratetraene-3,11B-diol17-one 3-acetate, 6B-methyl-18 nor D l1omo-1,3,5(10),13(17a)-estratetraene 3,11,8-diol-17-one 3-acetate, and 6-methyl-18-nor-D homo 1,3,5(10),6,13 (17a)-estrapentaene-3,11fi-diol-l7-one 3-acetate are each subjected to the action of a culture of F lavobacterium dehydrogenans according to the procedure of Example 9 to give respectively 165-methyl-18-nor-D homo 1,3,5 10) 32 13(l7a)-estratetraene-3,11fi-diol-17-one, 16/3 bromo-18- nor D-homo-1,3,5(10),13(17a)-estratetraene3,1lfl-diol- 17-one, 16x-bromo-18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,1 1fi-diol-17-one, 6/3-methyl-18-nor-D-homo- 1,3,5(10) ,13(17a)-estratetraene-3,11B-di0l-17 one and 6- methyl-1,3,5(l0) ,6,13 (17a) estrapentaene-3,11fi-diol-17- one.

To 0.5 g. of 18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,l1,6,16a-triol-17-one 3,16-diacetate in 30 ml. of methanol there is added 300 mg. of sodium carbonate. The reaction mixture is stirred over night at room temperature then added to 100 ml. of water and neutralized with acetic acid. The aqueous mixture is filtered and the filtrate extracted with methylene chloride. Methylene chloride extracts are combined, dried over sodium sulfate, then concentrated in vacuo to a residue containing 18-nor- D-homo-1,3 ,5(10),13(17a)-estratetraene-3,11B,16a triol- 17-one.

EXAMPLE 24 9a-halogeno-11B-hydr0xy-],3,5 (10)-estratrienes and 1 9-n0r-4-androstenes A. 3-meth0xy-1,3,5 (10),9(11 )-estratelraene-17-one. In a manner similar to that described in Example 21B 3- methoxy-1,3,5(10)-estratriene-115-01-17 one in pyridine is reacted with methanesulfonyl chloride and the resultant product isolated as described to give 3-methoxy-1,3,5 (10), 9(11)-estratetraen=-17-one.

B. 3-meth0xy-9a-br0m0-1,3,5(10) estratriene-I 1I3-0l- 17-0ne.-To a solution of 1 gram of 3-methoxy-1,3,5(10), 9(11)-estratetraene-17-one in 100 ml. of dioxane is added 10 m1. of water, 515 mg. of N-bromoacetamide and 4 ml. of 1.5 N-perchloric acid. The mixture is stirred at room temperature for 4 hours then 1 gram of sodium sulfite in 10 ml. of water is added and the solution extracted with methylene chloride. The extracts are washed with water, dried and concentrated in vacuo to a residue which is crystallized from methylene chloride-pentane to give 3-methoxy-9 a-bromo-1,3 ,5 (10)-estratriene-l1fi ol-17-one.

C. 3-meth0xy 95,11/3 0xid01,3,5(10)-estratriene-17- Una-A solution of 1 gram of 3-methoxy-9a-bromo1,3,5 (10)-estratriene-1lfi-ol-17-one in 50 ml. of acetone is heated at reflux temperature for 5 hours with 1 gram of potassium acetate. The acetone is distilled in vacuo, the resultant residue is triturated with water. A solid separates which is filtered from ether-pentane to give 3- methoxy-9fi,11fl-oxido-1,3,5(10)-estratriene-17-one.

D. 3-methoxy-9a-flu0r0-1,3,5 (10)-estratriene 11/3 ol- 17-0ne.-To a solution of 500 mg. of the 913,115-oxidoestratriene of Example 24C in 20 ml. of alcohol-free chloroform there is added at 0 C. a molar excess of a solution of hydrogen fluoride in 2:1 tetrahydrofuranchloroform. The mixture is kept at 0 C. for 4 hours, then is poured into ice water, neutralized with sodium carbonate, and extracted with methylene chloride. The organic extracts are washed with water then concentrated in vacuo to a residue which is crystallized from methylene chloride-pentane to give 3-methoxy-9a-fiuoro-1,3,5,(10) estratriene-l1B-ol-17-one.

E. 3-meth0xy-9a-chl0r0-1,3,5 (10)-estratriene 3,8 ol- ]7-0ne.3-methoxy-9,B,11B-oxido1,3,5,(10) estratriene- 17-one in chloroform is reacted with anhydrous hydrogen chloride in the manner described in Example 21F to give 3-methoxy-9a-chloro-1,3,5(10) estratriene 11B o1 17- one.

Similarly, the following llfi-hydroxy-estratriene and 1lfi-hydroxy-19-nor-4-androstenes are each subjected to a series of reactions described in Examples 24A-E whereby there is obtained the corresponding 9a-halogeno derivatives, i.e., the t-bIOInO, 9zx-flu010, and 9a-Chl0r0 derivatives thereof;

1,3,5'( 10 -estratriene-3,1 1fl-diol-17-one B-acetate, 3-methoxy-16fi-methyl-1,3,5,( 10)-estratriene-1 113-01- 17-one,

33 16,8-methyl- 1,3 ,5 10 -estratriene-3,1 1 B-diol- 17-one 3-acetate, 16a-bromo-1,3,5(10)-estratriene-3,1 1fi-diol-17-one 3-acetate, 6B-methyl1,3,5(10)-estratriene-3 ,1lfi-diol-17-one 3-acetate, 6u-flu0ro-1,3,5(10)-estratriene-3,11fi-diol-17-one 3-acetate, 19-nor-4-androstene-1 1,6-ol-3,17-dione, 6fi-fluoro-19-nor-4-androstene-11fl-ol-3 ,17-dione and 16fi-methyl- 19-nor-4-androstene-1 1 18-01-3, 17-dione.

EXAMPLE 25 9a-hal0gen0-18-n0r-D-hom0-13 (1 7a -dehydroestratrienes and 19-n0r-4-andr0stenes A. 3-m|ethOxy-Qu-haIOgenw-I8n0r-D-h0m0+1,3,5 (10 13=(17a)-eslratetraene-11p-ol-17-0ne.--3 methoxy 90cfluoro-1,3,5(10)-estratriene-1lfl-ol-l7-one is reacted with nitrosyl chloride in pyridine in the manner similar to that described in Example 1A. The'resultant product is isolated as described to give 3-methoxy-9a-fluorol,3,5(10)- estratriene-l1fl-ol-17-one ll-nitrite which is dissolved in benzene then irradiated with a 200 watt mercury lamp in the manner described in Example 23D. The resultant product is isolated in the manner similar to the described to give 3-methoxy-9a-fluoro-l8-nor-D-homo 1,3,5(10),- 13 17a)-estratetraene-1 1fi-ol-17-one.

Similarly, 3-methoxy-9u-chloro 1,3,5 (10) estratriene- 11fi-ol-17-one and 3-methoXy-9a-bromo-1,3,5 10)-estratriene-11B-ol-17-one are each converted to their respective 11-nitrite esters which upon irradiation with ultraviolet light according to the process of Example 23D yields 3- methxy-9u-chloro-18-nor-D homo 1,3,5 ,13(17a)- estratetraene-11fl-ol-17-one, and 3-methoxy-9u-bromo-18- nor-D-homo-1,3,5 (10),13 17a) estratetraene 116-01-17- one.

B. By going through a similar sequence of reaction as is described in Example 25A the 9u-halogeno-llfl-hydroxyestratriene and 19-nor-4-androstenes prepared as described in Example 24 are each converted to their respective 11- nitrite esters and then irradiated with a 200 watt mercury lamp to yield the corresponding 18-nor-D-homo-13(17a)- dehydro derivativesrespectively, i.e.,

9a-fluoro-18-nor-D-homo-1,3 ,5 (10)-estratriene-3,11fidiol' 17 -one 3-acetate,

3-methoxy-9a-fluoro-16fl-methyl-18-nor-D-homo- 1,3,5 10) ,13 17a)-estratetraene-1 1 (3-01-17 -one,

9a-fiuoro-166-bromo-18-nor-D-homo-1,3,5(10),13(17a)- estratetraene-3 ,1 1fl-dio1-17-one 3-acetate,

90L-fluO1O-16OL-bIOmO-18-I10r-D-hOH10-L3 ,5 10) ,13 17a)- estratetraene-3,11p-diol-17-one 3-acetate,

6;.3-methyl-9a-fluoro- 1 8-nor-D-homo- 1,3 ,5 10) ,1 3 17a) estratetraene-3 ,11B-diol-17-one 3-acetate,

6a,9a-difluoro-18-nor-D-h0mo-1,3,5(10),13(17a)- estratetraene-3,11l3-diol-17-one S-acetate,

9a-fiuoro-1 8,19-bis-nor-D-homo-4,l3 (17a)-androstadiene-11fi-0l-3 ,17-dione,

9OL-fll1OI'O-16fl-I1'l6thYl-1 8,19-bis-nor-D-homo-4,13 17a androstadiene-11B-ol-3 17 -dione and their corresponding 9a-Ci1l010, and 9a-bromo derivatives.

3 cording to the procedure of Example 9 and there is obtained, respectively, fiuoro 18 nor D homo- 1,3,5(10),l3(17a)-estratetraene-3,1lfi-diol 17 one, 9e.- fluoro-l6fi-bromo-18-nor D homo 1,3,5(10),13(17a)- estratetraene-3,1 1Bdiol-17-one, 9CL-flll01O-16OL-bIOII10-18- nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,11p diol- 17-one, 6 3-methyl-9a-fluor0-18-nor-D homo 1,3,5(10),- 13(17a)-estratetraene-3,1lfl-diol 17 one and 606,9 difluoro-lS-nor-D-homo 1,3,5(10),13 (17a) estratetraenc- 3,11,6-diol-17-one.

EXAMPLE 26 1 6a-hydroxy-18-nor-D-hydn0-1 lp-hydroxy-androstanes and estranes A. Preparation of 11B,16a-dihydr0xy androstanes and estranesfislant washings taken from a culture of a microorganism designated as Streptomyces halstedii (A.T.C.C. 13,499) are inoculated into a sterile nutrient medium having the following composition:

. Grams Cerelose (dextrose hydrate) 10 Yeast extract 5 NZ Amine B (enzymatic digest of casein) 10 Calcium carbonate 1 Distilled water in sufiicient volume tor a 1000 ml.

solution.

The above inoculated medium is then adjusted to a pH of 6.7 with potassium hydroxide and incubation subsequent-ly carried out at 28 C. for 48 hours via a rotary shaker. There is thus formed a suitable pre-grown inocu'lum for purposes of seeding,

A two liter portion of sterile nutrient medium of the composition described above contained in a 4-liter fermenting vessel is :autoclaved at 122 C./20 lbs. per sq. in.

for 60 minutes, then cooled to room temperature. Five percent of the pre-grown inoculum prepared .as described in the first paragraph above is then introduced into the medium with constant agitation being maintained. The fermentation is then conducted at 28 C. for 24 hours, employing an aeration rate of one-half volume of air per volume of broth per minute and maintaining a constant agitation rate of 1700 r.-p.m.

After completion of a 24-hour growth period, the heavy myceliurn so obtained is removed by passing the whole broth through a filter system consisting of glass wool and gauze. The isolated mycelium is then suspended in two liters of tap water contained in a fermentation pot equipped with a stirring apparatus. To the stirred suspension there is added 250 mg. of 4-androstene-11fi-ol-3, 17-dione dissolved in a minimum amount of acetoneethanol (1 :1 by volume). The fermentation is continued under the same conditions as previously described for 16 hours. At the end of this time, the whole broth is successively extracted with three equivalent volumes of methyl isobutyl ketone. The combined solvent extracts are then concentrated in vacuo to a residue which is crystallized cfirom ethyl acetate to give 4-androstene-11,8,16u,diol-3,17- dione.

Other steroid substrates such as 1,4-androstadiene-11B-ol-3,17-dione and the 6OL-flll01'0 analog thereof, 9a-bromo-4-androstene-1 1B-ol-3,17-dione, 4,6-androstadiene-1 lfi-ol-3,'17-dio11e, Sa-I-an-drostene-1 1 8-ol-3,17-dione and the '9a-fluoro-analog thereof,

1,4,-6-androstatriene-1 1fl-ol-3,17-dione, 6a-methyl-4-androstene-1i 3-01-3,17-dione, 6a-fiu0ro-4-androstene-1'15-01-3,17-dione, 6B-fluoro-4-androstene-1'1fl-ol-3,17-dione, 19-nor-4-andr-ostene-11B-ol-3,-17-dione and the 6a-fluoro analog thereof, 2ot-methyl-9ot-i0do-4,6-andro:stadiene-1 1,8-ol-3,17-dione, 3-methoxy-1,3,5(10)-estratriene-11B-ol-17-one, 3-acet-oxy-1,3,5(10)-estratriene-11/3-ol-17-one and the 35 6a-fluoro analog thereof, and 3-acetoxy-6,B-methyl-9u-fiuoro-1,3,S(10)-est-ratriene-11,8-

ol-17-one and the 9a-fluoro-analog thereof are each individually subjected to the action of Streptomyces halstedii (A.T.C.C. 13,499) in the manner described above. derivative of the respective steroid substrate is obtained.

B. Preparation of the 11 -nitrite-1 oot-acetoxy intermediates.-Each of the 11;3,16ot-dihydroxy intermediates prepared as described in Example 26A is reacted with acetic anhydride in pyridine in the manner described in Example 23B and there is obtained the corresponding 160cracetate ester; each of which is reacted with nitrosyl chloride in pyridine in the manner described in Example 1A to give the respective 11-nitrite-16-acet-ate ester intermediate, i.e.,

4-an-drostene-11fl,16a-diol-3,17-dione ll-nitrite 16-acetate,

1,4-androstadiene-11fl,16a-diol-3,7-dione 1 l-nitrite 16- acetate and the 6u-fluoro analog thereof,

9a-bromo-4-androstene-11fi,16u-diol-3 17 -dione ll-nitrite 16-acetate,

4,6-androstad-iene-11fl,16a-diol-3,17-dione ll-nitrite 16- acetate,

Sa-I-androstene-l1/3,16u-diol-3,17-dione ll-nitrite 16- acetate and the 9u-fluoro analog thereof,

1,4,6-androstatriene-1 1/5,16u-diol-3,17-dione 1 l-nitrite I-G-acetate,

6a-methyl-4androstene-1 1[3,16ot-diol-3,17-dione ll-nitrite 16-acetate,

6a-fiuoro-4-androstene-1=1fl,16a-di0l-3,17-dione l l-nitrite 16-acetate,

6fl-fluoro-4-androstene-11 8,16a-dio1-3,17-dione ll-nitrite 16-acetate,

ot-fluoro-analog thereof,

2a-methyl-9ot-iodo-4,6-androstadiene-1lfi,l6a-diol-3,17-

dione ll-nitrite 16-acetate,

3-methoxy-1,3,5 10) -estratriene-1 lfi, 160t-diO1-17-OI16 11- nitrite 16-acetate,

3-acetoxy-,3,5(10)-estnatriene-11,8,16ot-diol-17-one 11- nitrite 16-acetate and the 606-flL10l'O rand GB-rnethyl analog thereof and 3-acetoxy-6fi-methyl-9wfluoro43,5 10)-e-stratriene-11 fl,

16wdio1-17-one 1 l-nitrite 16-acetate. I

C. Preparation of the 16a-acer0xy-18-n0r-D-h0m0-13 (17a)-dehydro-andr0stanes and estranes.Each of the ll-nitrite 16-acetate ester intermediates prepared as described in Example 27B is individually irradiated with a 200 watt mercury lamp provided with a Pyrex filter in a manner similar to that described in Example 8A and there is obtained respectively 18-nor-D-homo-4,13 17a) -androstadiene-1 1B,16a-diol- 3,17-dioue 16-acetate,

18-nor-D-homo-1,4,13(117a)-androstatriene-11,8,16a-diol- 3,17-dione 16-acetate and the 6a-fluoro analog thereof,

9u-bromo-1 8-nor-D-homo-4,13 17a) -androstadiene-1 1B,

16a-diol-3,17-dione 16-acetate,

18-nor-D-homo-4,6,13 17 a) -androstatriene- 1-1 13,16zx-Ciil- 3,17-dione l6-acetate,

18-nor-D-homo-5 (IL-1,13 17a) -androstadiene-1 1 [3,16adiol-3,17-dione and the 9a-fiuoro-analog thereof,

18-nor-D-homo-1,4,6,13(17a)-androstatetraene-113,160:-

diol-3,17-dione .1'6-acetate,

6ot-methyl-18-nor-D-homo-'4, 13 17a) -androstadiene- 11B,16a-diol-3,l7-dione 16-acetate,

6a-fluoro-18-nor-D-homo-4,13 (17a)-androstadiene-11B,

16oc-di0l-3,17-di0ne 16-acetate and the 6B-fiuoro-epimer thereof,

18,19-bis-nor-D-homo-11fi,16a-diol-3,17-dione 16-acetate and the 6a-fiuoro analog thereof,

In each case the corresponding l6a-hydroxylated Eta 2a-methyl-9a-iodo-18-nor-D-horno-4,6,13 (17a)-androstatriene- 1'1 5, 1 6oc-diOl-3 ,17-dione 16-acetate, 3-methoxy-18-nor-D-hon1o-1,3,'5(10),13(17a)-estratetraene-l1p,16e-diol-17-one\16-acetate, 18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-3,115,

16u-triol-17-one 3,16-diacetate and the 6a-fluoro analog thereof and the 6,8-methyl analog and the 6,8-methyl-9a-flu0r0-18-nor-D- homo-1,3,5(10),13(17a)-estratetraene-3,115,16a-triol- 17-one 3,16-diacetate.

D. Hydrolysis of ester gr0ups.A 16-acetoxy-18-nor- D-homo-steroid, prepared as described in Example 260, is hydrolyzed with sodium carbonate in methanol in the manner similar to that described in Example 23E and there is obtained the corresponding 16u-hydroxy steroid. Other ester groups present such as the 3-acetoxy are also hydrolyzed to the corresponding 3-hydroxy steroid.

EXAMPLE 27 Preparation of 11-ket0-18-nor-D-h0m0 13 (1 7a) -dehydr0- androstanes and pregnanes A. 18-n0r-D-h0m0 4,13(17a)-andr0stadiene 3,11,17- trione (tautomeric forms 18-n0r-D-h0m0-4,12,17a(17)- androstafriene-17-0l-3Jl-dione, and 18 nor D-homo- 4,11,13(17a)-androstatriene-11-0l-3,17-di0ne).To a S0- lution of 500 mg. of 18-nor-D-h0mo-4,13(17a)-androstadiene-11fi-ol-3,17-dione in 200 ml. of purified acetone chilled to 5 C. is added dropwise with stirring 0.45 ml. (109 percent of theory) of chromic/sulfuric acid reagent (266 mg. chromic acid per ml.). The mixture is stirred at 5 C. for 5 minutes then diluted with water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with water, and concentrated in vacuo to a residue which is crystallized from acetone-ether to give 18-nor-D-homo-4,13(17a)-androstadiene-3 ,1 1,17-trione.

B. In a similar manner, by utilizing the above procedure each of the l l/s-hydroxy-l8-nor-D-homo-androstanes and estranes prepared as described in the preceding examples may be oxidized to the corresponding ll-keto derivative and its tautomeric forms. For example,

18-nor-D-homo-1,4,13 (17a)-androstatriene-3,1 1,17-trione and the 9a-fluoro analog thereof,

18-nor-D-homo-4,6,13 (17a)-androstatriene-3,1 1,17-

trione,

18-nor-D-homo-1,4,6,13(17a)-androstatetraene3,11,17-

trione,

18-nor-D-homo-5a-L13 (17a)-androstadiene-3;11,17-

trione,

3-acetoxy-18-nor-D-homo-5,13 17a) -androstadiene- 11,17-dione,

18,19-bis-norD-homo-4,13(17a)-androstadiene-3 ,11,17-

trione,

3-methoxy-18-nor-D-homo-1,3,5(10),13(17a)-estratetraene-11,17-dione and 3 -acetoxy- 1 8-nor-D-homo- 1,3 ,5(10),13(17a)-estratetraene-11,17-dione are each derived from the corresponding ll-hydroxy derivatives by oxidation with chromic/sulfuric acid.

C. Esterification of the enol tautomeric forms of 18- n0r-D-h0m0-4,13 (17a)-andr0stadiene-3,11,l7-tri0ne. A solution of mg. of 18-nor-D-homo-4,13(17a)-androstadiene-3,11,17-trione (prepared as described in Example 27A) in 2 ml. of pyridine and 0.2 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. The reaction mixture is then poured into ice water and the resultant precipitate filtered, Washed with water, dried and crystallized from acetone-hexane to yield a mixture of the acetate esters of the tautomeric forms of the starting compound namely, a mixture of 1l-acetoxy-l8-nor-D-homo- 4,11,13(17a)-androstatriene-3,17-dione and 17-acetoxy- 18-nor-D-homo-4,'12,17a(17)-estratriene-3,1l-dione with the latter 17-acetoxy ester predominating.

By substituting other alkanoic acid esters, such as butyric and caproic acid in the above procedure there is obtained the corresponding butyrate ad caproate ester mixtures at C-11 and C17 respectively.

In a similar manner, each of the 11, 17-diketo-18-n-or- D-homo-13(17a)-dehydroandrostanes and estranes, prepared as described in Example 27A, may be esterified according to the procedure of this example and there is obtained a mixture of the esters of the tautomeric forms, namely, the corresponding 1l-acyloxy-17-ket0-18-nor-D- homo-11,13(17a)-bisdehydroandrostanes or estranes and the 11 keto-17-acyloxy-18-nor-D-homo-12,17a(17)-bisdehydroandrostanes or estranes. For example, 3-methoxy 18 nor-D-homo-l,3,5(),13(17a)-estratetraene- 11,17-dione upon reaction with caproic anhydride in pyridine yields a mixture of 3-methoxy-ll-caproyloxy-18-nor- D homo-l,3-,5(10),11,13(17a)-estrapentaene-17-one and 3 methoxy-l7-caproyloxy-18-nor-D-homo-1,3,5(10),l2, l7a(17 -estrapentaene ll-one.

EXAMPLE 28 Preparation of 11 dehydro-1 8-n0r-D-hom0-l 3 (1 7a) dehydroandrostanes and estranes A. 18 n0r-D-h0m0-4,11,13(17a)-andr0statriene-3,17- dione.-A suspension of 100 mg. of 18-nor-D-homo-4,13 (l7a)-androstadiene-1lfl-ol-3,l7-dione (the compound of Example 1) in 7 ml. of methanol containing 0.5 m1. of perchloric acid is stirred at room temperature for 18 hours. The resulting solution is poured into water and the aqueous mixture extracted with methylene chloride. The organic extracts are combined, washed with water and sodium bicarbonate solution, dried, and concentrated in vacuo to a residue which is crystallized twice from acetonehexane to give 18-nor-D-homo-4,11,13(17a)-androstatriene-3,l7-dione, M.P. 189-192 C;

9OL-fl1lOI'O-1S-IIOP-D-hOIIIOalfi-J. 1,13 17a)-androstatetraene-3 l7-dione,

18-nor-D-homo-4,6,1 1, l 3 17a -androstatetraene-3, 17-

dione,

18nor-D-homo-1,4,6,l 1,13 l7a)-androstapentaene-3, l7-

dione,

18-nor-D-homo-5u-1,l1,13(17a)-androstatriene-3 l7- dione,

3-acetoxy-18-n0r-D-homo-5,l 1,13 17a -androstatriene- 17-one,

18,l9-bis-nor-D-h0mo-4,l1,13(17a)-andr0statriene-3 ,17-

dione,

3-methoxy-l8-nor-D-homo-1,3,5(10),11,13(17a)-estrapentaene- 17-one are each derived from the corresponding ll-hydroxy derilvative by dehydration with perchloric acid in methano Ester groups present in the molecule prior to dehydration with perchloric acid in methanol will be hydrolyzed during the reaction carried out according to the procedure of Example 28A. Thus, for example, 18-nor-D-homo- 1,3,5 (10) ,13 l7a)-estratetraene-'3,1 1fi-diol-17-one 3-acetate and 18-nor-D-homo-5,13 17a) -androstadiene-3p, 1 1p- ,estrapentaene-3 0l-17-one and 18-n0r-D-homo-5,ll,13

( 17a) -androstatriene-3,6-ol-17-one respectively.

EXAMPLE 29 Preparation of 1 1 -esters of 1.1 -hydr0xy-1 8-n0r-D-h0m0- 13 (1 7a) -dehydr0andr0stanes and estranes A. 18 nor D-h0m0-4,Z3 (17a)-androstadiene-1Ifl-ol- 3,1'7-dione-I1-acetate and the 1 -dehydro analog thereof.- 100 mg. of 18-nor-D-horno-4,13(17a)-androstadiene-1 1,6- ol-3,17-dione in 3 ml. of pyridine and /2 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. The reaction mixture is poured into ice water and extracted with methylene chloride. The organic extracts are combined, washed with' water, then concentrated to a residue which is recrystallized from acetone-hexane to give 18 nor-D-homo-4,13(17a)androstadiene-llB-ol-3, l7-dione ll-acetate, M.P. 161-165 C.

[041D +148 (CHCla); Mitt? 239 m (634,000)

18 nor D homo-1,4,13(17a)-androstatriene-l1,8-01- 3,17-dione (the compound of Example 2) is reacted with acetic anhydride in pyridine in the above manner to give 18 nor-D-homo-l,4,13(l7a)-androstatriene-11,6-ol-3,l7- dione ll-acetate M.P. 199-201" C.

[00D (011013); ixzg 240 m (632,000)

In a similar manner, by substituting the acid anhydrides of other lower alkanoic acids, such as, propio-nic, valeric, t-butyl acetic acid, for acetic anhydride in the above procedure there isobtained the corresponding ll-propionate, ll-valerate or ll-t-butyl acetate of 18-nor-D- homo-4,13(17a)-androstadiene-1lfl-ol-3,17-dione and 18- nor D-iomo-l,4-l3(17a)-androstatriene-11fl-ol-3,l7-dione respectively.

B. 18 nor D-h0m0-4,13(17a)-zmdr0stadierte-11e-0l- 3,17 diane 11-benzoate.l8-nor-D-homo-4,13(17a)- androstadiene-llfi-ol-3,17-dione is reacted with benzoyl chloride in pyridine in a manner similar to that described in Example 29A. The resultant product is isolated as described and crystallized from acetone-hexane to give 18 nor-D-homo-4,13(l7a)-androstadiene-11fl-o1-3,17-dione ll-benzoate.

In a similar manner, by substituting o-toluyl chloride, m-toluyl chloride or p-toluyl chloride for benzoyl chloride in the above procedure there is obtained the corresponding 11-o-, m,- or p-toluate of l8-nor-D-homo-4,13- 17a) -androstadie-nel l5-ol-3,l7-dione.

C. 18 nor D-hom0-4,Z3(17a)-andr0stadiene-11fi-0l 3,17 dione-JI-methyl sulfonate.By substituting methanesulfonyl chloride forbenzoyl chloride in the procedure of Example 293 18-nor-D-homo-4,l3(17a)-androstadiene-l15-ol-3,17-dione is converted to the corresponding ll-methanesulfonate ester.

In a similar manner, 18-n0r-D-homo-4,l3(17a)-androstadiene-lle-ol-3,l7-dione is reacted with p-toluenesulfonyl chloride in pyridine to give 18 nor-D-h0mo-4,l3- (17a) -androstadiene-1 1fl-ol-3,17-dione ll-p-toluenesulfonate.

D. 18 nor D-h0m0-4,13(17a)-androstadiene-11,B-0l- 3,17-di0ne-11-hemisuccinate.To 1 gram of 18-nor-D- homo 4,13( 17a)-androstadiene-ll,8-ol-3,17-dione in 10 ml. of pyridine is added 1 gram of succinic anhydride. The mixture is heated on a steam bath for 1 hour then cooled and diluted with water. A solid separates which is filtered, washed with water, and dried to give 18-nor-D- homo 4,l3(l7a) androstadiene-llfi-ol-3,l7-dione 11- hemisuccinate.

Similarly, 3-methoxy-18-nor D homo 1,3,5 (10},13 (17a)-estratetraene-183-01-l7-one and 18-nor-D homo- 5,13(I17a)-androstadiene-3fi,1'1fl-diol=17-0ne 3-acetate are reacted with succinic anhydride in pyridine inthe above described manner to give respectively 3-methoxy-18-nor- D-homo-1,3,5(l0),13(17a)-estratetraene-1lfi-ol 17 one 39 ll-hemisuccinate and l8-nor-D-homo-5,l3(l7a)-androstadiene3fi, l 1,8-diol-17-one 3-acetate ll-hemisuccinate.

E. Similarly, by utilizing the procedures of Examples 29A-D each of the 1lfl-hydroxy-l8-nor-D-homo-androstanes and estranes, prepared as described in any of the preceding examples may be converted to their corresponding ll-carboxylic acid ester or ll-sulfonic acid ester respectively. It will be apparent to one skilled in the art that any other free hydroxyl groups present in the molecule will also be esterified as Well as the ll-hydroxy group.

EXAMPLE 30 Preparation of various mixed esters and hydrolysis thereof A. (1) l8-nor-D homo 5,13(17a) androstadiene- 3,8,l6a-triol-17-one 3,16-diacetate, prepared as described in Example 22B, is reacted with benzoyl chloride in pyridine in the manner described in Example 2913 to give l8-nor-D homo 5,13(17a) androstadiene-3fl,l1 3,16a triol-l7-one 3,16-diacetate ll-benzoate.

(2) By substituting methanesulfonyl chloride for benzoyl chloride in the procedure described in the preceding paragraph there is obtained 18 nor D homo- 5,-13(17a)-androstadiene 35,115,160; triol 17 one 3,16- diacetate ll-methanesulfonate.

(3) To 1 gram of l8-nor-D-homo-5,13(l7a)-androstadiene-3,B,llB,16ot-triol-17-one 3,16-diacetate l1 benzoate in 30 ml. of methanol is added 300 mg. of sodium carbonate. The reaction mixture is stirred for 18 hours at room temperature then added to 100 ml. of water and neutralized with acetic acid. The aqueous mixture is filtered then extracted with methylene chloride. The methylene chloride extracts are combined and concentrated in vacuo to a residue containing 18-nor-D-hom0- 5,13(l7a)-androstadiene-3fl-l1,l6a-triol 17 one ll-benzoate.

In a similar manner the ll-methanesulfonate ester, prepared in Example 30A(2), is hydrolyzed with sodium carbonate in methanol to give 18-nor-D-homo-5,13(17a)- androstadiene-3;8,11B,16ot-triol-17 one 11 methanesulfonate.

(4) When an ester such as 18-nor-D-homo-5,13(17a)- androstadiene-3fl,116,16u-triol-17-one 3,16-diacetate 11- benzoate is reacted with perchloric acid in methanol according to the procedure described in Example 28A dehydration at C-ll occurs as well as hydrolysis of the ester and there is obtained l8-nor-D-homo 5,11,13(17a)-an drostatriene-3/3,16u-diol-17-one.

In a similar manner 18-n0r-D-homo-5,13(l7a)-androstadiene-3/3,11,8,16a-triol-17-one 3,16-diacetate 11 methanesulfonate upon reaction with perchloride acid in methanol yields l8-nor-D-homo-5,1l,13(17a) andrstadiene 3fl,l6ot-dioll7-one.

B. (1) 18-nor-D-homo 1,3,5(10),(17a) estratetraene-3,11B-diol-l7-one 3-acetate (the compound of Example 8) is reacted'with benzoyl chloride in pyridine in the manner of Example 29B to give l8-nor D homo- 1,3,5(10),13(17a)-estratetracne-3, 1l/3-diol 17 one 3- acetate ll-benzoate.

(2) 18-nor-D-homo 1,3,5(10),13(17a)) estratetraene-3,11;-diol-17-one 3-benzoate (the compound of Example 8B) is reacted with acetic anhydride in pyridine according to the procedure of Example 29A to give 18- nor-D-homo-l,3,5 (l0),13(17a)-estratetraene 3,116 diol- 17-one 3-benzoate ll-acetate.

(3) Each of the above described mixed 3,11-diesters may be subjected to the action of a culture of Flavobizcterium dehydrogenans and there will be obtained 18- nor D homo-1,3,5(l0),l3(17a) estratetraene 3,11 3- diol 17 one 11 benzoate and 18 nor D homo- 1:, 5(:10),13(17a)-estratetraene-3,l lp dio1-17 one 3- benzoate respectively.

(4) Alternatively, when the 3-acetate ll-benzoate mixed diester, prepared as in Example 3.1 is hydrolyzed with sodium carbonate in methanol according to the procedure described in Example 30(3) there is obtained 18- nor-D-homo 1,3,5(10),13(17a) estratetraene- 3,11 3 diol-l7-one ll-benzoate.

From the foregoing, it Will be obvious to one skilled in the art that a great variety of esters may be prepared depending on the choice of reagents and sequence of reactions.

It is to be understood that this invention is not to be limited to the exact details of operation or exact compounds as shown and described herein as obvious modifications and equivalents will be apparent to one skilled in the art. The invention is to be limited only by the scope of the appended claims.

We claim:

1. A member selected from the group consisting of:

hydro-4-androstene-3-one, the 19-nor-, A 13 A A -4,5-dihydroanalogs thereof, and the 2-methyl and 7-methyl-homologs of the foregoing; '3,B-(OW)-9a-X-16 V 17 keto 1'8 nor D homo- 13 17a)-dehydro-5-androstene;

3-(OR)-6-B-9a-Xa16-V-17 keto l8 nor D homo- 13 (.17a)-dehydro-1,3,5('10)-estratriene;

and the tautomers of the foregoing;

wherein B is a member of the group consisting of hydrogen, a-lower alkyl, S-lower alkyl, oc-fiIlOIO and 8-fluoro; X is a member of the group consisting of hydrogen and halogen; V is a member of the group consisting of hydrogen, a-lower alkyl, ,B-lower alkyl, tat-halogen selected from the group consisting of fluorine, chlorine, and bromine, ,B-halogen selected from the group consisting of fluorine, chlorine, and bromine; and zx-OY, wherein Y is a member of the group consisting of hydrogen and an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of an alkanoic acid and an aryl carboxylic acid; R is a member of the group consisting of hydrogen, lower alkyl, and an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of an alkanoic acid and an aryl carboxylic acid; W is a member of the group consisting of hydrogen and an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms selected from the group consisting of an alkanoic acid and an aryl carboxylic acid;

said member being characterized by a configuration about 011 and 012 of the group consisting of:

wherein A is a member selected from the group consisting of hydrogen and an acid radical of an acid selected from the group consisting of an aryl carboxylic acid having up to 8 carbon atoms, and a saturated aliphatic hydrocarbon carboxylic acid having up to eight carbon atoms.

2. 3 OR 18 nor-D-homo-1,3,5(l0), 13(17a)-estra- 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF: 6-B-9A-X-16-V-17-KETO-18-NOR - D - HOMO - 13(17A)DEHYDRO-4-ANDROSTENE-3-ONE, THE 19-NOR, $1-, $6-, $1,6-, $1-4,5-DIHYDRO- ANALOGS THEREOF, AND THE 2-METHYL AND 7-METHYL-HOMOLOGS OF THE FOREGOING; 3B-(OW)-9A-X-16- V - 17 - KETO - 18 - NOR - D - HOMO13(17A)-DEHYDRO-5-ANDROSTENE; 3-(OR)-6-B-9A-X-16-V-17 - KETO - 18 - NOR - D - HOMO13(17A)-DEHYDRO-1,3,5(10)-ESTRATRIENE; AND THE TAUTOMERS OF THE FOREGOING; WHEREIN B IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, A-LOWER ALKYL, B-LOWER ALKYL, A-FLUORO AND B-FLUORO; X IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND HALOGEN; V IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, A-LOWER ALKYL, B-LOWER ALKYL, A-HALOGEN SELECTED FROM THE GROUP CONSISTING OF FLUORINE, CHLORINE, AND BROMINE, B-HALOGEN SELECTED FROM THE GROUP CONSISTING OF FLUORINE, CHLORINE, AND BROMINE; AND A-OY, WHEREIN Y IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF AN ALKANOIC ACID AND AN ARYL CARBOXYLIC ACID; R IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, AND AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF AN ALKANOIC ACID AND AN ARYL CARBOXYLIC ACID; W IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF AN ALKANOIC ACID AND AN ARYL CARBOXYLIC ACID; SAID MEMBER BEING CHARACTERIZED BY A CONFIGURATION ABOUT C-11 AND C-12 OF THE GROUP CONSISTING OF:
 16. IN THE PROCESS OF PREPARING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 6-B - 9A - X-16-V-17-KETO-18-NOR-D-HOMO-13(17A)-DEHYDRO-4-ANDROSTENE-3-ONE, THE 19-NOR-,$1-, $6-, $1,6-, $1-4,5-DIHYDRO- ANALOGS THEREOF, AND THE 2-METHYL AND 7-METHYL-HOMOLOGS OF THE FOREGOING; 3B - (OW) - 9A - X - 16 - V - 17-KETO-18-NOR-D-HOMO-13 (17A)-DEHYDRO-5-ANDROSTENE; 3 - (OR) - 6 -B - 9A - X - 16 - V - 17-KETO-18-NOR-DHOMO-13(17A)-DEHYDRO-1,3,5(10)-ESTRATRIENE; AND THE TAUTOMERS OF THE FOREGOING; WHEREIN, B IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, A-LOWER ALKYL, B-LOWER ALKYL, A-FLUORO AND BFLUORO; X IS A MEMBER OF A GROUP CONSISTING OF HYDROGEN AND HALOGEN; V IS A MEMBER OF A GROP CONSISTING OF HYDROGEN, A-LOWER ALKYL, B-LOWER ALKYL, A-HALOGEN HAVING AN ATOMIC WEIGHT LESS THAN 126, BHALOGEN HAVING AN ATOMIC WEIGHT LESS TAHN 126, AND A-OY, WHEREIN Y IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF AN ALKANOIC ACID AND AN ARYLCARBOXYLIC ACID; R IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, AND AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOM S SELECTED FROM THE GROUP CONSISTING OF AN ALKANOIC ACID AND AN ARYLCARBOXYLIC ACID; W IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND AN ACID RADICAL OF A HYDROCARBON CARBOXYLIC ACID HAVING UP TO 8 CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF AN AN ALKANOIC ACID AND AN ARYLCARBOXYLIC ACID; SAID COMPOUND BEING CHARACTERIZED BY A CONFIGURATION ABOUT C-11 AND C-12 OF THE GROUP CONSISTING OF: 